TY - JOUR
AU1 - Tomé-Carneiro,, João
AU2 - Crespo, María, Carmen
AU3 - López, de las Hazas, María Carmen
AU4 - Visioli,, Francesco
AU5 - Dávalos,, Alberto
AB - Abstract Consumption of highly processed foods, such as those high in trans fats and free sugars, coupled with sedentarism and chronic stress increases the risk of obesity and cardiometabolic disorders, while adherence to a Mediterranean diet is inversely associated with the prevalence of such diseases. Olive oil is the main source of fat in the Mediterranean diet. Data accumulated thus far show consumption of extra virgin, (poly)phenol-rich olive oil to be associated with specific health benefits. Of note, recommendations for consumption based on health claims refer to the phenolic content of extra virgin olive oil as beneficial. However, even though foods rich in monounsaturated fatty acids, such as olive oil, are healthier than foods rich in saturated and trans fats, their inordinate use can lead to adverse effects on health. The aim of this review was to summarize the data on olive oil consumption worldwide and to critically examine the literature on the potential adverse effects of olive oil and its main components, particularly any effects on lipid metabolism. As demonstrated by substantial evidence, extra virgin olive oil is healthful and should be preferentially used within the context of a balanced diet, but excessive consumption may lead to adverse consequences. dietary habits, fatty acids, fatty liver, hydroxytyrosol, lipid metabolism, olive oil INTRODUCTION Dietary habits are strongly influenced by geographical, environmental, social, and, often, economic factors.1 Unhealthy dietary habits include the frequent consumption of processed foods, sugar-sweetened beverages, and nutritionally poor, cheap, edible oils.2 In the last 3 decades, portion size has increased remarkably,3 leading to excessive intake of food and calories. Consequently, the prevalence of chronic diseases such as diabetes, hypertension, and obesity is increasing.4 However, a direct relationship between changes in eating behavior and the increase in the incidence of chronic diseases did not begin to be calculated until the early 1990s.5,6 The Mediterranean diet is one of the healthiest dietary patterns.7 Olive oil, obtained from olives (Olea europaea, family Oleaceae) is the main source of lipids in Mediterranean countries. The quality of olive oil depends on different operative parameters and technical considerations in the extraction process and changes over the course of the storage period until the oil is consumed.8 According to the International Olive Council standards, virgin olive oils (VOOs) are oils obtained solely by mechanical or other physical means under conditions—particularly thermal conditions—that do not lead to alterations in the oil. Moreover, VOOs may not undergo any treatment other than washing, decantation, centrifugation, and filtration. Olive oils are designated as virgin if their free acidity, expressed as oleic acid, does not exceed 2% and they have only minor organoleptic defects compared with extra virgin olive oils. Virgin olive oils are classified as extra virgin if their free acidity does not exceed 0.8% and they are free of organoleptic defects. If, at production, acidity surpasses 3.3%, olive oils must be refined, or rectified, resulting in a substantial reduction in the concentration of their minor constituents. Hence, refined olive oil and EVOO belong to 2 different commercial categories.9 Olive oil consumption is not confined to Mediterranean areas and has increased worldwide during the last 25 years.10 There is unequivocal evidence that EVOO exerts numerous healthful actions. On the basis of such evidence, the advice to use olive oil preferentially for cooking and dressings is scientifically sound.11–14 Nevertheless, even though foods rich in monounsaturated fats, eg, olive oil, are less harmful than foods containing saturated and trans fats, their unrestricted consumption is not without consequences, particularly since the effects of very high consumption are not clearly established. Of note, many studies are performed with high, unrealistic doses of oil, fatty acids, or (poly)phenols, which is commonplace in the field of human nutrition. Here, the intent was to critically review the potential risks of excessive olive oil consumption in the context of lipid metabolism and to explore the role that specific components of olive oil may play in the development of different chronic disorders. TYPICAL OLIVE OIL CONSUMPTION Olive oil consumption in several countries worldwide was estimated by combining International Olive Council statistics10,15,16 with demographic data17 (Table 1).15,16 Data on the average of the 4 most recent olive oil seasons show the top 4 olive oil–consuming countries worldwide to be Greece (≈ 36 mL/person/day), Spain (≈ 31 mL/person/day), Italy (≈ 26 mL/person/day), and Portugal (≈ 21 mL/person/day). In Spain, olive oil consumption in 2017 was estimated to be 7.5 L/person/year, allocated as follows: 2.5 L of EVOO, 1.15 L of VOO, and 3.84 L of refined olive oil. Average olive oil consumption in the United States over the last 4 years was approximately 3 mL/person/day, which is more modest compared with consumption in Mediterranean and North African countries and Australia, but not negligible.18 Table 1 Annual olive oil consumption (2016–2019) in 15 countries worldwide Year . Olive oil consumption . Spain . France . Greece . Italy . Portugal . USA . Algeria . Morocco . Tunisia . Turkey . China . Japan . Syria . Brazil . Australia . 2016 Consumption (tonnes × 10−3)15,16,a 494.5 113.4 140.0 598.1 70.0 321.0 80.0 120.0 35.0 116.0 39.0 53.5 104.0 42.0 50.0 Population (×10−6)17 46.63 64.67 10.62 60.66 10.33 323.02 40.55 35.13 11.30 79.83 1414.05 127.76 17.47 206.16 24.26 Kilograms/person/year 10.60 1.75 13.19 9.86 6.78 0.99 1.97 3.42 3.10 1.45 0.03 0.42 5.95 0.20 2.06 Milliliters/person/dayb 31.72 5.24 39.45 29.49 20.28 2.97 5.90 10.22 9.26 4.35 0.08 1.25 17.81 0.61 6.16 2017 Consumption (tonnes × 10−3) 454.4 94.0 105.0 438.9 70.0 315.0 67.0 120.0 21.0 150.0 44.0 54.5 98.0 45.0 59.5 Population (× 10−6) 46.65 64.84 10.57 60.67 10.29 325.09 41.39 35.58 11.43 81.12 1421.02 127.50 17.10 207.83 24.59 Kilograms/person/year 9.74 1.45 9.93 7.23 6.80 0.97 1.62 3.37 1.84 1.85 0.03 0.43 5.73 0.22 2.42 Milliliters/person/day 29.14 4.34 29.71 21.64 20.35 2.90 4.84 10.09 5.49 5.53 0.09 1.28 17.15 0.65 7.24 2018 Consumption (tonnes × 10−3) 470.0 111.0 130.0 560.7 80.0 315.0 78.5 120.0 33.0 176.5 46.0 55.5 87.0 46.0 76.5 Population (× 10−6) 46.69 64.99 10.52 60.63 10.26 327.10 42.23 36.03 11.57 82.34 1427.65 127.20 16.95 209.47 24.90 Kilograms/person/year 10.07 1.71 12.36 9.25 7.80 0.96 1.86 3.33 2.85 2.14 0.03 0.44 5.13 0.22 3.07 Milliliters/person/day 30.11 5.11 36.95 27.66 23.33 2.88 5.56 9.96 8.53 6.41 0.10 1.31 15.36 0.66 9.19 2019 Consumption (tonnes × 10−3) 525.0 81.0 130.0 500.0 75.0 315.5 78.0 140.0 30.0 163.0 48.0 55.0 87.0 47.0 78.0 Population (× 10−6) 46.74 65.13 10.47 60.55 10.23 329.07 43.05 36.47 11.70 83.43 1433.78 126.86 17.07 211.05 25.20 Kilograms/person/year 11.23 1.24 12.41 8.26 7.33 0.96 1.81 3.84 2.57 1.95 0.03 0.43 5.10 0.22 3.09 Milliliters/person/day 33.60 3.72 37.13 24.70 21.94 2.87 5.42 11.48 7.67 5.84 0.10 1.30 15.24 0.67 9.26 Year . Olive oil consumption . Spain . France . Greece . Italy . Portugal . USA . Algeria . Morocco . Tunisia . Turkey . China . Japan . Syria . Brazil . Australia . 2016 Consumption (tonnes × 10−3)15,16,a 494.5 113.4 140.0 598.1 70.0 321.0 80.0 120.0 35.0 116.0 39.0 53.5 104.0 42.0 50.0 Population (×10−6)17 46.63 64.67 10.62 60.66 10.33 323.02 40.55 35.13 11.30 79.83 1414.05 127.76 17.47 206.16 24.26 Kilograms/person/year 10.60 1.75 13.19 9.86 6.78 0.99 1.97 3.42 3.10 1.45 0.03 0.42 5.95 0.20 2.06 Milliliters/person/dayb 31.72 5.24 39.45 29.49 20.28 2.97 5.90 10.22 9.26 4.35 0.08 1.25 17.81 0.61 6.16 2017 Consumption (tonnes × 10−3) 454.4 94.0 105.0 438.9 70.0 315.0 67.0 120.0 21.0 150.0 44.0 54.5 98.0 45.0 59.5 Population (× 10−6) 46.65 64.84 10.57 60.67 10.29 325.09 41.39 35.58 11.43 81.12 1421.02 127.50 17.10 207.83 24.59 Kilograms/person/year 9.74 1.45 9.93 7.23 6.80 0.97 1.62 3.37 1.84 1.85 0.03 0.43 5.73 0.22 2.42 Milliliters/person/day 29.14 4.34 29.71 21.64 20.35 2.90 4.84 10.09 5.49 5.53 0.09 1.28 17.15 0.65 7.24 2018 Consumption (tonnes × 10−3) 470.0 111.0 130.0 560.7 80.0 315.0 78.5 120.0 33.0 176.5 46.0 55.5 87.0 46.0 76.5 Population (× 10−6) 46.69 64.99 10.52 60.63 10.26 327.10 42.23 36.03 11.57 82.34 1427.65 127.20 16.95 209.47 24.90 Kilograms/person/year 10.07 1.71 12.36 9.25 7.80 0.96 1.86 3.33 2.85 2.14 0.03 0.44 5.13 0.22 3.07 Milliliters/person/day 30.11 5.11 36.95 27.66 23.33 2.88 5.56 9.96 8.53 6.41 0.10 1.31 15.36 0.66 9.19 2019 Consumption (tonnes × 10−3) 525.0 81.0 130.0 500.0 75.0 315.5 78.0 140.0 30.0 163.0 48.0 55.0 87.0 47.0 78.0 Population (× 10−6) 46.74 65.13 10.47 60.55 10.23 329.07 43.05 36.47 11.70 83.43 1433.78 126.86 17.07 211.05 25.20 Kilograms/person/year 11.23 1.24 12.41 8.26 7.33 0.96 1.81 3.84 2.57 1.95 0.03 0.43 5.10 0.22 3.09 Milliliters/person/day 33.60 3.72 37.13 24.70 21.94 2.87 5.42 11.48 7.67 5.84 0.10 1.30 15.24 0.67 9.26 a Olive crop year calculated from October 1 (previous year) to September 30. Open in new tab Table 1 Annual olive oil consumption (2016–2019) in 15 countries worldwide Year . Olive oil consumption . Spain . France . Greece . Italy . Portugal . USA . Algeria . Morocco . Tunisia . Turkey . China . Japan . Syria . Brazil . Australia . 2016 Consumption (tonnes × 10−3)15,16,a 494.5 113.4 140.0 598.1 70.0 321.0 80.0 120.0 35.0 116.0 39.0 53.5 104.0 42.0 50.0 Population (×10−6)17 46.63 64.67 10.62 60.66 10.33 323.02 40.55 35.13 11.30 79.83 1414.05 127.76 17.47 206.16 24.26 Kilograms/person/year 10.60 1.75 13.19 9.86 6.78 0.99 1.97 3.42 3.10 1.45 0.03 0.42 5.95 0.20 2.06 Milliliters/person/dayb 31.72 5.24 39.45 29.49 20.28 2.97 5.90 10.22 9.26 4.35 0.08 1.25 17.81 0.61 6.16 2017 Consumption (tonnes × 10−3) 454.4 94.0 105.0 438.9 70.0 315.0 67.0 120.0 21.0 150.0 44.0 54.5 98.0 45.0 59.5 Population (× 10−6) 46.65 64.84 10.57 60.67 10.29 325.09 41.39 35.58 11.43 81.12 1421.02 127.50 17.10 207.83 24.59 Kilograms/person/year 9.74 1.45 9.93 7.23 6.80 0.97 1.62 3.37 1.84 1.85 0.03 0.43 5.73 0.22 2.42 Milliliters/person/day 29.14 4.34 29.71 21.64 20.35 2.90 4.84 10.09 5.49 5.53 0.09 1.28 17.15 0.65 7.24 2018 Consumption (tonnes × 10−3) 470.0 111.0 130.0 560.7 80.0 315.0 78.5 120.0 33.0 176.5 46.0 55.5 87.0 46.0 76.5 Population (× 10−6) 46.69 64.99 10.52 60.63 10.26 327.10 42.23 36.03 11.57 82.34 1427.65 127.20 16.95 209.47 24.90 Kilograms/person/year 10.07 1.71 12.36 9.25 7.80 0.96 1.86 3.33 2.85 2.14 0.03 0.44 5.13 0.22 3.07 Milliliters/person/day 30.11 5.11 36.95 27.66 23.33 2.88 5.56 9.96 8.53 6.41 0.10 1.31 15.36 0.66 9.19 2019 Consumption (tonnes × 10−3) 525.0 81.0 130.0 500.0 75.0 315.5 78.0 140.0 30.0 163.0 48.0 55.0 87.0 47.0 78.0 Population (× 10−6) 46.74 65.13 10.47 60.55 10.23 329.07 43.05 36.47 11.70 83.43 1433.78 126.86 17.07 211.05 25.20 Kilograms/person/year 11.23 1.24 12.41 8.26 7.33 0.96 1.81 3.84 2.57 1.95 0.03 0.43 5.10 0.22 3.09 Milliliters/person/day 33.60 3.72 37.13 24.70 21.94 2.87 5.42 11.48 7.67 5.84 0.10 1.30 15.24 0.67 9.26 Year . Olive oil consumption . Spain . France . Greece . Italy . Portugal . USA . Algeria . Morocco . Tunisia . Turkey . China . Japan . Syria . Brazil . Australia . 2016 Consumption (tonnes × 10−3)15,16,a 494.5 113.4 140.0 598.1 70.0 321.0 80.0 120.0 35.0 116.0 39.0 53.5 104.0 42.0 50.0 Population (×10−6)17 46.63 64.67 10.62 60.66 10.33 323.02 40.55 35.13 11.30 79.83 1414.05 127.76 17.47 206.16 24.26 Kilograms/person/year 10.60 1.75 13.19 9.86 6.78 0.99 1.97 3.42 3.10 1.45 0.03 0.42 5.95 0.20 2.06 Milliliters/person/dayb 31.72 5.24 39.45 29.49 20.28 2.97 5.90 10.22 9.26 4.35 0.08 1.25 17.81 0.61 6.16 2017 Consumption (tonnes × 10−3) 454.4 94.0 105.0 438.9 70.0 315.0 67.0 120.0 21.0 150.0 44.0 54.5 98.0 45.0 59.5 Population (× 10−6) 46.65 64.84 10.57 60.67 10.29 325.09 41.39 35.58 11.43 81.12 1421.02 127.50 17.10 207.83 24.59 Kilograms/person/year 9.74 1.45 9.93 7.23 6.80 0.97 1.62 3.37 1.84 1.85 0.03 0.43 5.73 0.22 2.42 Milliliters/person/day 29.14 4.34 29.71 21.64 20.35 2.90 4.84 10.09 5.49 5.53 0.09 1.28 17.15 0.65 7.24 2018 Consumption (tonnes × 10−3) 470.0 111.0 130.0 560.7 80.0 315.0 78.5 120.0 33.0 176.5 46.0 55.5 87.0 46.0 76.5 Population (× 10−6) 46.69 64.99 10.52 60.63 10.26 327.10 42.23 36.03 11.57 82.34 1427.65 127.20 16.95 209.47 24.90 Kilograms/person/year 10.07 1.71 12.36 9.25 7.80 0.96 1.86 3.33 2.85 2.14 0.03 0.44 5.13 0.22 3.07 Milliliters/person/day 30.11 5.11 36.95 27.66 23.33 2.88 5.56 9.96 8.53 6.41 0.10 1.31 15.36 0.66 9.19 2019 Consumption (tonnes × 10−3) 525.0 81.0 130.0 500.0 75.0 315.5 78.0 140.0 30.0 163.0 48.0 55.0 87.0 47.0 78.0 Population (× 10−6) 46.74 65.13 10.47 60.55 10.23 329.07 43.05 36.47 11.70 83.43 1433.78 126.86 17.07 211.05 25.20 Kilograms/person/year 11.23 1.24 12.41 8.26 7.33 0.96 1.81 3.84 2.57 1.95 0.03 0.43 5.10 0.22 3.09 Milliliters/person/day 33.60 3.72 37.13 24.70 21.94 2.87 5.42 11.48 7.67 5.84 0.10 1.30 15.24 0.67 9.26 a Olive crop year calculated from October 1 (previous year) to September 30. Open in new tab OLIVE OIL COMPONENTS Olive oils are composed of approximately 98% to 99% fatty acids, mainly triacylglycerol (TAG; also known as triglyceride) esters of oleic acid (55% to 83%), palmitic acid (7.5% to 20%), or linoleic acid (3.5% to 21%), along with other fatty acids such as stearic acid (0.5% to 5%).19 The fatty acid composition depends primarily on the cultivar of the olive. For example, the percentage of oleic acid, linoleic acid, and palmitic acid in the Arbequina olive is 64.73%, 12.80%, and 14.34%, respectively, whereas these values are 77.04%, 4.90%, and 10.63% for the Picual olive variety. Furthermore, the ratio of monounsaturated fatty acids (MUFAs) to polyunsaturated fatty acids (PUFAs) ranges between 4.94 and 13.94 for the Arbequina and Picual olive varieties, respectively.20 The stereospecificity of dietary TAGs influences their digestion and absorption.21 In most vegetable oils, TAGs contain unsaturated fatty acids at the sn-2 position.22 In olive oil, however, 50% of TAGs are composed of molecules of oleic acid in all 3 positions, whereas other, less common forms of esterification include the following: (1) 1 molecule of palmitic acid at the sn-3 position and 2 molecules of oleic acid at the sn-1 and sn-2 positions, and (2) 1 molecule of linoleic acid at the sn-2 position flanked by 2 molecules of oleic acid.19 The other 1% to 2% of fatty acids in olive oil are the saponifiable and unsaponifiable fractions. The former contains many different compounds such as sterols, squalene, volatile molecules, tocopherols, carotenes, chlorophylls, and aliphatic and triterpenic alcohols in different proportions.23 The soluble fraction is composed mainly of phenolic compounds, including phenolic acids, phenolic alcohols (hydroxytyrosol and tyrosol), secoiridoid structures (oleuropein, hydroxytyrosol linked to the dialdehydic form of elenolic acid [3,4-EDA]), and flavonoids.23 FACTORS THAT INFLUENCE OLIVE OIL COMPOSITION The components of olive oil vary, depending on procedures used during the handling of olives prior to processing. The refining of olive oil also affects composition. Unlike VOO and, especially, EVOO, refined olive oil lacks most of the minor components found in the saponifiable fraction. In particular, the content of phenolic compounds in olive oil depends on many factors, such as variety or cultivar of olive, degree of olive ripening, climatic conditions, soil, irrigation, technical processes used for oil separation (ie, temperature, beating time, addition of water, etc), and duration and conditions of storage.24–26 In addition, the accurate quantification of phenolic compounds in olive oil is extremely complicated because of the lack of both appropriate standards and a standardized method to analyze (poly)phenols.27 The oxidative stability of olive oil decreases during heating, resulting in the formation of hydroperoxides, conjugated dienes, carboxylic compounds, and conjugated trienes.20 In addition, heat modifies the fatty acid composition of olive oil by reducing the concentrations of palmitoleic, linoleic, linolenic, and oleic acids.20 Heat also reduces the content and, thus, the purported beneficial effects of tocopherols and phenolic compounds, which are the antioxidant components of olive oil.28 RECOMMENDATIONS FOR OLIVE OIL CONSUMPTION Substantial evidence links EVOO consumption with numerous beneficial health effects, especially within the context of a balanced Mediterranean diet (reviewed by Yubero-Serrano et al,11 Martinez-Gonzalez et al,29 and Foscolou et al30). Like all oils and fats, olive oil is highly caloric (9 kcal/g). It is important to remember that total fatty acids in olive oil include approximately 14% saturated fatty acids, in addition to roughly 73% MUFAs.19 According to the European Society of Cardiology/European Atherosclerosis Society guidelines,31 saturated fat intake should not exceed 10% of the total caloric intake for optimal effects on plasma lipid levels. In individuals with hypercholesterolemia, however, saturated fatty acid intake should be limited to less than 7% of total energy intake. The optimal diet should, hence, contain mostly MUFAs and both n-6 and n-3 PUFAs.32,33 The European Food Safety Authority (EFSA) recommendations for olive oil consumption are based on the phenolic content and the possible salubrious effects of olive oil on blood lipids, ie, protection from oxidative stress.34 Furthermore, the EFSA Panel on Dietetic Products, Nutrition and Allergies states that the recommended amounts of (poly)phenols should be provided by moderate amounts of olive oil, easily attainable with a balanced diet. Conditions for the use of EFSA health claim ID 1333 require the consumption of at least 2 spoonfuls (23 g) of olive oil per day for at least 3 weeks, within the context of a diet low in saturated fatty acids. Claims ID 1638 and ID 1639 specify the consumption of 20 g of olive oil with a (poly)phenol content of 200 mg/kg.34 The US Food and Drug Administration (FDA) published a controversial statement proclaiming that “limited and not conclusive scientific evidence suggests that eating about 2 tablespoons (23 g) of olive oil daily may reduce the risk of coronary heart disease due to the monounsaturated fat in olive oil.”35 “To achieve this possible benefit, olive oil is to replace a similar amount of saturated fat and not increase the total number of calories you eat in a day.”36 In the PREDIMED (PREvención con DIeta MEDiterránea) study, which addressed the effects of the Mediterranean diet in the primary prevention of cardiovascular disease, dietary recommendations included the consumption of at least 50 g (≈ 4 tablespoons) of EVOO per day. Despite having olive oil intakes higher than those recommended by the EFSA/FDA, participants were subjected to a monthly dietary control to avoid any excessive calorie intake.37 Current evidence does not allow a determination of what might constitute a harmful level of olive oil intake. Such a determination will depend, for instance, on an individual’s dietary pattern, particularly with regard to the profile of fat consumed. Since the recommendation for oil consumption in a 2000-calorie diet is 27 g (≈ 30 mL or 2 tablespoons in the case of olive oil) per day, it is conceivable that higher amounts could have adverse effects on health if the daily recommendation for fat-derived calorie intake has already been attained. For example, in Mediterranean countries, the dietary pattern is shifting from Mediterranean to Westernized.38,39 In a Spanish population, a compensatory dietary pattern has been documented in individuals who have adopted an unhealthy Western-based dietary pattern but try to compensate by adding purportedly healthy foodstuffs, eg, olive oil, to their habitual diet.40 POTENTIAL ADVERSE EFFECTS OF EXCESSIVE OLIVE OIL CONSUMPTION ON LIPID METABOLISM As mentioned above, an inordinate intake of olive oil (or any other oil or fat) may have deleterious health effects, especially by increasing the risk of cardiometabolic disorders such as hypercholesterolemia. To review this topic, PubMed and Scopus databases were searched for studies reporting adverse effects associated with olive oil consumption. The following keywords were used: “olive oil AND lipid metabolism,” “olive oil AND triglycerides,” “olive oil AND cholesterol,” “olive oil AND lipid synthesis,” “olive oil AND lipid profile,” and “olive oil AND lipoprotein.” Articles were critically reviewed, and those reporting adverse in vivo effects related to lipid metabolism in both healthy and disease-induced models were summarized (Table 2).41–70 Table 2 Potential adverse effects of olive oil on lipid metabolism in animal and human studies Reference . Species . Model/intervention . Potential adverse effects . Arbones-Mainar et al (2007)41 Mouse 24 female Apoe−/− mice. Standard mouse chow supplemented with 0.15% (wt/wt) cholesterol and 1 of the following: 20% (wt/wt) Picual EVOO (90 mg of (poly)phenols/kg), 20% (wt/wt) Arbequina EVOO (25 mg of (poly)phenols/kg), or 20% (wt/wt) palm oil Olive oil increased both hepatic fat content and adipophilin levels, though Picual olive oil decreased plasma TAGs Ferramosca et al (2008)42 Mouse 50 male ICR mice. Fed for 8 wk with standard diet supplemented with 7.5% olive oil or 7.5% corn oil ↑Hepatic TAGs, TC, and phospholipids in olive oil-fed animals in the eighth week compared to baseline Thuy et al (2001)43 Mouse Male C3H/He mice. Fed for 50 wk with olive oil, safflower oil, or linseed oil diet Plasmatic and hepatic TC and TAGs were increased in the olive oil group Oliván et al (2014)44 Mouse SOD1G93A mice. 3 experimental groups: standard chow diet; chow diet enriched with 20% (wt/wt) EVOO; and chow diet containing 20% palm oil. Fed for 8 wk Compared with controls, mice receiving the high-fat diets showed increased plasma cholesterol levels Acín et al (2007)45 Mouse 26 apoE-deficient mice. Fed chow diet, diet supplemented with standard olive oil devoid of phenolic compounds, or diet supplemented with test olive oil enriched with linoleic acid, phytosterols, tocopherols, triterpenes, and waxes for 11 wk Plasma TC and LDL-C levels increased in mice fed a diet supplemented with standard olive oil Liao et al (2010)46 Hamster Male Golden Syrian hamsters. Randomly assigned to control or obesity groups for 4 wk (period for HFD-induced obesity). For another 8 wk, controls were fed a low-fat diet, but obese mice were switched to a low-fat diet and subdivided into an obesity-control group, a high-MUFA oil with a high ratio of polyunsaturated to saturated fats group, and an olive oil group The olive oil group had significantly increased plasma TC levels compared with the control group and the obesity control group and the highest plasma HDL-C levels among all groups after 8 wk Djohan et al (2019)47 Rat 32 young male Wistar rats. Four groups: 1 was fed control diet (11% energy from fat) and 3 were fed high-fat diets rich in crude or refined palm oils or in olive oil (56% energy from fat) for 12 wk Rats fed the olive oil diet showed hepatic TAG accumulation, inflammation, and cytolysis Duavy et al (2017)48 Rat 15 male Wistar rats (300 g). For 60 d, animals were fed 4% cholesterol-free soybean oil; 1% HCD + 12% oleic acid–rich olive oil; or 1% HCD+12% linoleic acid–rich sunflower oil Rats fed HCD + olive oil showed a decrease in serum LDL-C, VLDL-C, and TC levels compared with rats fed HCD + sunflower oil. However, rats fed HCD + olive oil showed microvesicular steatosis in the hepatic acinar zone 1 Macri et al (2015)49 Rat 80 male weanling Wistar rats. Diets were rich in MUFA oils and contained 20 g of fat per 100 g of diet: AIN-93G (control diet); EVOO + control diet; high-oleic sunflower oil + control diet; or atherogenic diet for 8 wk; the remaining 2 groups received the atherogenic diet for 3 wk, and then the saturated fat was replaced by an oil mixture of soybean oil plus olive oil or high-oleic sunflower oil for 5 wk Rats consuming MUFA-rich diets after the atherogenic diet showed the highest hepatic index and the highest body fat, epididymal fat, intestinal fat, and perirenal fat Ruiz-Gutiérrez et al (2001)50 Rat 40 spontaneously hypertensive rats. Each group was fed 1 of the following diets for 12 wk: a basal diet (control) or the basal diet supplemented with 10% (wt/wt) olive oil, 10% (wt/wt) high-oleic sunflower oil, or 10% (wt/wt) fish oil Compared with controls, olive oil diet led to increases in plasma and hepatic TAGs, TC, and phospholipids Buettner et al (2013)51 Rat Male Wistar rats. Rats (n = 5/group) were fed for 8 wk with standard rodent chow (fat content, 11% energy); atherogenic diet containing 15% neutral fat, 1.25% cholesterol, and 0.5% cholate by mass; atherogenic diet without cholesterol; atherogenic diet without choline; atherogenic diet without cholate; atherogenic diet with olive oil, or atherogenic diet with coconut oil After 8 wk, rats fed the atherogenic diet plus olive oil showed increased TAG levels compared with rats fed the atherogenic diet Adamopoulos et al (1996)52 Rat Male Wistar albino rats. 4 groups of 10 rats each were fed for 40 d. Control group received a nonpurified diet; other 3 groups received the nonpurified diet enriched with fat (14 g fat/100 g diet): egg yolk, olive oil, or safflower oil Olive oil group showed increased TC and TAG levels compared with controls Katsarou et al (2015)53 Rat 64 male Wistar rats. One group was fed an HCD (2 g cholesterol), while 5 other groups were fed a diet supplemented with 10% oils or oil products: HCD + EVOO; HCD + sunflower oil; HCD + high-oleic sunflower oil; HCD + phenolic-deprived EVOO; HCD + sunflower oil enriched with EVOO phenolics; or HCD + high-oleic sunflower oil enriched with EVOO phenolics Groups receiving EVOO, phenolic-deprived EVOO, high-oleic sunflower oil, or high-oleic sunflower oil enriched with EVOO phenolics showed increased serum TC and LDL-C compared with cholesterol-fed group Dulloo et al (1995)54 Rat 48 Sprague-Dawley male rats. Refeeding for 10 d after a 2-wk period of low food intake consisting of a low-fat diet or HFDs that varied in type of fat: lard; coconut oil; olive oil; safflower oil; fish oil; or mixed fats Plasma cholesterol increased in groups fed the HFD + olive oil or the HFD + lard compared with group fed the low-fat diet Jeffery et al (1996)55 Rat Weanling male Lewis rats. Rats fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control Olive oil diet resulted in increased serum TAGs compared with low-fat diet or safflower oil diets. HFD resulted in increased serum TC with HFD Oladapo et al (2017)56 Rat 30 male diabetic Wistar rats. 8-wk intervention with different oils. 5 groups: control diet; diabetic control diet; 10% palm oil–enriched diet; 10% soya oil–enriched diet; or 10% olive oil–enriched diet The group fed olive oil had the highest level of TC and non-HDL-C, the lowest level of HDL-C, and the highest atherogenic index Sasase et al (2007)57 Rat Spontaneously Diabetic Torii rats. Olive oil was administrated orally at 5 mL/kg in a fat absorption test. Blood samples were collected at 0 h, 3 h, and 6 h Elevation of TAGs in plasma and lymph chylomicron was increased in Spontaneously Diabetic Torii rats Deng et al (2004)58 Rat Male hyperinsulinemic corpulent JCR:LA-cp rats. 3 groups, each with 3 obese rats and 3 lean rats, were fed 1 of the following: a control diet (10% of calories from olive oil), an olive oil–enriched diet (40% of calories from olive oil), or a fish oil–enriched diet (40% of calories from menhaden oil) for 2 wk Plasma TAGs were increased in corpulent rats fed the olive oil diet compared with corpulent control rats Mori et al (1997)59 Rat Male OLETF rats (model of spontaneous noninsulin-dependent diabetes mellitus) assigned to 1 of 5 groups of 12 rats each: lard; olive oil; safflower oil; eicosapentaenoic acid ethyl ester (each fed at a daily dose of 0.3 g/kg); or distilled water (controls, 0.3 mL/kg/d) for 17 or 18 wk Increased TAG content in plasma, muscle, and liver in the olive oil group compared with the control group. Increased TC, phospholipids, and free fatty acid levels in olive oil–treated rats compared with control rats Maki et al (2015)60 Human 54 men and women with hypercholesterolemia. Double-blind, randomized, crossover design. 4 tablespoons (≈ 54 g) of corn oil (528 mg phytosterols, 29.7 g PUFAs) or EVOO (120 mg phytosterols, 5.6 g PUFAs) per day was provided in 3 servings of study product per day as part of a weight maintenance diet TAG concentrations increased from baseline in both groups, especially in the EVOO group (13.0% increase), although statistical significance was not reported Vogel et al (2000)61 Human 10 healthy, normolipidemic individuals. 3 meals with different sources of fat added: EVOO (50 g), canola oil (50 g), or canned red salmon; and 2 meals containing olive oil and antioxidant vitamins and foods Mean serum TAGs increased after each meal. The EVOO meal with no added foods or vitamins decreased endothelial function postprandially Abia et al (1999)62 Human 8 healthy normolipidemic individuals. Participants ingested a meal rich in virgin olive oil (70 g). Fasting (0 h) and postprandial blood samples were collected hourly for 7 h Plasma and lipoprotein TAG concentrations increased quickly over fasting values and peaked twice at 2 h and 6 h during the 7-h postprandial period Fitó et al (2002)63 Human 16 healthy volunteers. Participants ingested 50 mL of virgin olive oil in a single dose. Blood samples were collected from 0 to 24 h Serum TAG, plasma fatty acids, and lipid peroxidation products increased in plasma and VLDL-C, reaching a peak at 4–6 h and returning to baseline values at 24 h Rueda-Clausen et al (2007)64 Human 10 healthy young men. Participants were randomly assigned to receive 60 mL of soybean, olive, or palm oil, administered once weekly in a soup meal for 9 wk All meals resulted in a similar postprandial increase in TAGs, independent of the type of oil consumed Stonehouse et al (2015)65 Human 28 overweight/obese men. Volunteers consumed, in random order 1 wk apart, isocaloric high-protein, high-fat meals prepared with either 40 g of palmolein or 40 g of olive oil after an overnight fast Postprandial serum TAG concentrations increased Tholstrup et al (2011)66 Human 10 healthy women. Randomized, crossover, postprandial study. Volunteers consumed test meals containing 1 g of fat per kilogram of body weight (mean intake, 62 g). Meals prepared with either cocoa butter high in stearic acid or olive oil Both meals resulted in a significant increase in serum TAG concentrations over time Sanchez-Rodriguez et al (2018)67 Human 58 healthy individuals. 3-wk randomized, crossover, controlled, double-blind, intervention study. Participants received a daily dose (30 mL) of the following: virgin olive oil containing 124 ppm of phenolic compounds and 86 ppm of triterpenes; OVOO enriched with triterpenes (490 ppm of phenolic compounds and 86 ppm of triterpenes); or OVOO without most phenolic compounds Fasting plasma TAG concentrations increased after the virgin olive oil and OVOO interventions. Noteworthy, plasma TAGs were low at baseline (78 ± 5 mg/dL) Sun et al (2018)68 Human 20 healthy Chinese men. Randomized, controlled, single-blinded crossover study. Participants consumed 6 isocaloric meals containing 40 g of SFAs (butter), MUFAs (olive oil), or PUFAs (grapeseed oil) and 50 g of either low-glycemic index (basmati rice) or high-glycemic index (jasmine rice) carbohydrate Serum TAG concentrations increased postprandially Jackson et al (2002)69 Human 9 healthy postmenopausal women. Single-blind randomized within-subject crossover study. Participants consumed 1 of 4 test meals (40 g fat) containing oils with different fatty acid composition: palm oil, rich in SFAs; safflower oil, rich in n-6 PUFAs; 1:1 (vol/vol) mixture of deodorized highly purified fish oil and safflower oil, rich in long-chain PUFAs; and olive oil, rich in n-9 MUFAs Olive oil resulted in an increased apolipoprotein B-48 response compared with the other dietary oils following sequential test meals Perez-Jimenez et al (1995)70 Human 21 healthy, normolipidemic, young males. Volunteers consumed an NCEP-I diet (30% of energy as fat) during a 25-d period. Individuals were then assigned to two 4-wk study periods, according to a randomized, crossover design. Group 1 consumed an olive oil–enriched diet (40% fat, 22% MUFAs) for 4 wk, followed by a sunflower oil–enriched diet (40% fat, 22% MUFAs) for 4 wk. Group 2 consumed these diets in the reverse order The olive oil diet resulted in increased TC, LDL-C, HDL-C, and apolipoprotein A-I compared with the NCEP-I diet Reference . Species . Model/intervention . Potential adverse effects . Arbones-Mainar et al (2007)41 Mouse 24 female Apoe−/− mice. Standard mouse chow supplemented with 0.15% (wt/wt) cholesterol and 1 of the following: 20% (wt/wt) Picual EVOO (90 mg of (poly)phenols/kg), 20% (wt/wt) Arbequina EVOO (25 mg of (poly)phenols/kg), or 20% (wt/wt) palm oil Olive oil increased both hepatic fat content and adipophilin levels, though Picual olive oil decreased plasma TAGs Ferramosca et al (2008)42 Mouse 50 male ICR mice. Fed for 8 wk with standard diet supplemented with 7.5% olive oil or 7.5% corn oil ↑Hepatic TAGs, TC, and phospholipids in olive oil-fed animals in the eighth week compared to baseline Thuy et al (2001)43 Mouse Male C3H/He mice. Fed for 50 wk with olive oil, safflower oil, or linseed oil diet Plasmatic and hepatic TC and TAGs were increased in the olive oil group Oliván et al (2014)44 Mouse SOD1G93A mice. 3 experimental groups: standard chow diet; chow diet enriched with 20% (wt/wt) EVOO; and chow diet containing 20% palm oil. Fed for 8 wk Compared with controls, mice receiving the high-fat diets showed increased plasma cholesterol levels Acín et al (2007)45 Mouse 26 apoE-deficient mice. Fed chow diet, diet supplemented with standard olive oil devoid of phenolic compounds, or diet supplemented with test olive oil enriched with linoleic acid, phytosterols, tocopherols, triterpenes, and waxes for 11 wk Plasma TC and LDL-C levels increased in mice fed a diet supplemented with standard olive oil Liao et al (2010)46 Hamster Male Golden Syrian hamsters. Randomly assigned to control or obesity groups for 4 wk (period for HFD-induced obesity). For another 8 wk, controls were fed a low-fat diet, but obese mice were switched to a low-fat diet and subdivided into an obesity-control group, a high-MUFA oil with a high ratio of polyunsaturated to saturated fats group, and an olive oil group The olive oil group had significantly increased plasma TC levels compared with the control group and the obesity control group and the highest plasma HDL-C levels among all groups after 8 wk Djohan et al (2019)47 Rat 32 young male Wistar rats. Four groups: 1 was fed control diet (11% energy from fat) and 3 were fed high-fat diets rich in crude or refined palm oils or in olive oil (56% energy from fat) for 12 wk Rats fed the olive oil diet showed hepatic TAG accumulation, inflammation, and cytolysis Duavy et al (2017)48 Rat 15 male Wistar rats (300 g). For 60 d, animals were fed 4% cholesterol-free soybean oil; 1% HCD + 12% oleic acid–rich olive oil; or 1% HCD+12% linoleic acid–rich sunflower oil Rats fed HCD + olive oil showed a decrease in serum LDL-C, VLDL-C, and TC levels compared with rats fed HCD + sunflower oil. However, rats fed HCD + olive oil showed microvesicular steatosis in the hepatic acinar zone 1 Macri et al (2015)49 Rat 80 male weanling Wistar rats. Diets were rich in MUFA oils and contained 20 g of fat per 100 g of diet: AIN-93G (control diet); EVOO + control diet; high-oleic sunflower oil + control diet; or atherogenic diet for 8 wk; the remaining 2 groups received the atherogenic diet for 3 wk, and then the saturated fat was replaced by an oil mixture of soybean oil plus olive oil or high-oleic sunflower oil for 5 wk Rats consuming MUFA-rich diets after the atherogenic diet showed the highest hepatic index and the highest body fat, epididymal fat, intestinal fat, and perirenal fat Ruiz-Gutiérrez et al (2001)50 Rat 40 spontaneously hypertensive rats. Each group was fed 1 of the following diets for 12 wk: a basal diet (control) or the basal diet supplemented with 10% (wt/wt) olive oil, 10% (wt/wt) high-oleic sunflower oil, or 10% (wt/wt) fish oil Compared with controls, olive oil diet led to increases in plasma and hepatic TAGs, TC, and phospholipids Buettner et al (2013)51 Rat Male Wistar rats. Rats (n = 5/group) were fed for 8 wk with standard rodent chow (fat content, 11% energy); atherogenic diet containing 15% neutral fat, 1.25% cholesterol, and 0.5% cholate by mass; atherogenic diet without cholesterol; atherogenic diet without choline; atherogenic diet without cholate; atherogenic diet with olive oil, or atherogenic diet with coconut oil After 8 wk, rats fed the atherogenic diet plus olive oil showed increased TAG levels compared with rats fed the atherogenic diet Adamopoulos et al (1996)52 Rat Male Wistar albino rats. 4 groups of 10 rats each were fed for 40 d. Control group received a nonpurified diet; other 3 groups received the nonpurified diet enriched with fat (14 g fat/100 g diet): egg yolk, olive oil, or safflower oil Olive oil group showed increased TC and TAG levels compared with controls Katsarou et al (2015)53 Rat 64 male Wistar rats. One group was fed an HCD (2 g cholesterol), while 5 other groups were fed a diet supplemented with 10% oils or oil products: HCD + EVOO; HCD + sunflower oil; HCD + high-oleic sunflower oil; HCD + phenolic-deprived EVOO; HCD + sunflower oil enriched with EVOO phenolics; or HCD + high-oleic sunflower oil enriched with EVOO phenolics Groups receiving EVOO, phenolic-deprived EVOO, high-oleic sunflower oil, or high-oleic sunflower oil enriched with EVOO phenolics showed increased serum TC and LDL-C compared with cholesterol-fed group Dulloo et al (1995)54 Rat 48 Sprague-Dawley male rats. Refeeding for 10 d after a 2-wk period of low food intake consisting of a low-fat diet or HFDs that varied in type of fat: lard; coconut oil; olive oil; safflower oil; fish oil; or mixed fats Plasma cholesterol increased in groups fed the HFD + olive oil or the HFD + lard compared with group fed the low-fat diet Jeffery et al (1996)55 Rat Weanling male Lewis rats. Rats fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control Olive oil diet resulted in increased serum TAGs compared with low-fat diet or safflower oil diets. HFD resulted in increased serum TC with HFD Oladapo et al (2017)56 Rat 30 male diabetic Wistar rats. 8-wk intervention with different oils. 5 groups: control diet; diabetic control diet; 10% palm oil–enriched diet; 10% soya oil–enriched diet; or 10% olive oil–enriched diet The group fed olive oil had the highest level of TC and non-HDL-C, the lowest level of HDL-C, and the highest atherogenic index Sasase et al (2007)57 Rat Spontaneously Diabetic Torii rats. Olive oil was administrated orally at 5 mL/kg in a fat absorption test. Blood samples were collected at 0 h, 3 h, and 6 h Elevation of TAGs in plasma and lymph chylomicron was increased in Spontaneously Diabetic Torii rats Deng et al (2004)58 Rat Male hyperinsulinemic corpulent JCR:LA-cp rats. 3 groups, each with 3 obese rats and 3 lean rats, were fed 1 of the following: a control diet (10% of calories from olive oil), an olive oil–enriched diet (40% of calories from olive oil), or a fish oil–enriched diet (40% of calories from menhaden oil) for 2 wk Plasma TAGs were increased in corpulent rats fed the olive oil diet compared with corpulent control rats Mori et al (1997)59 Rat Male OLETF rats (model of spontaneous noninsulin-dependent diabetes mellitus) assigned to 1 of 5 groups of 12 rats each: lard; olive oil; safflower oil; eicosapentaenoic acid ethyl ester (each fed at a daily dose of 0.3 g/kg); or distilled water (controls, 0.3 mL/kg/d) for 17 or 18 wk Increased TAG content in plasma, muscle, and liver in the olive oil group compared with the control group. Increased TC, phospholipids, and free fatty acid levels in olive oil–treated rats compared with control rats Maki et al (2015)60 Human 54 men and women with hypercholesterolemia. Double-blind, randomized, crossover design. 4 tablespoons (≈ 54 g) of corn oil (528 mg phytosterols, 29.7 g PUFAs) or EVOO (120 mg phytosterols, 5.6 g PUFAs) per day was provided in 3 servings of study product per day as part of a weight maintenance diet TAG concentrations increased from baseline in both groups, especially in the EVOO group (13.0% increase), although statistical significance was not reported Vogel et al (2000)61 Human 10 healthy, normolipidemic individuals. 3 meals with different sources of fat added: EVOO (50 g), canola oil (50 g), or canned red salmon; and 2 meals containing olive oil and antioxidant vitamins and foods Mean serum TAGs increased after each meal. The EVOO meal with no added foods or vitamins decreased endothelial function postprandially Abia et al (1999)62 Human 8 healthy normolipidemic individuals. Participants ingested a meal rich in virgin olive oil (70 g). Fasting (0 h) and postprandial blood samples were collected hourly for 7 h Plasma and lipoprotein TAG concentrations increased quickly over fasting values and peaked twice at 2 h and 6 h during the 7-h postprandial period Fitó et al (2002)63 Human 16 healthy volunteers. Participants ingested 50 mL of virgin olive oil in a single dose. Blood samples were collected from 0 to 24 h Serum TAG, plasma fatty acids, and lipid peroxidation products increased in plasma and VLDL-C, reaching a peak at 4–6 h and returning to baseline values at 24 h Rueda-Clausen et al (2007)64 Human 10 healthy young men. Participants were randomly assigned to receive 60 mL of soybean, olive, or palm oil, administered once weekly in a soup meal for 9 wk All meals resulted in a similar postprandial increase in TAGs, independent of the type of oil consumed Stonehouse et al (2015)65 Human 28 overweight/obese men. Volunteers consumed, in random order 1 wk apart, isocaloric high-protein, high-fat meals prepared with either 40 g of palmolein or 40 g of olive oil after an overnight fast Postprandial serum TAG concentrations increased Tholstrup et al (2011)66 Human 10 healthy women. Randomized, crossover, postprandial study. Volunteers consumed test meals containing 1 g of fat per kilogram of body weight (mean intake, 62 g). Meals prepared with either cocoa butter high in stearic acid or olive oil Both meals resulted in a significant increase in serum TAG concentrations over time Sanchez-Rodriguez et al (2018)67 Human 58 healthy individuals. 3-wk randomized, crossover, controlled, double-blind, intervention study. Participants received a daily dose (30 mL) of the following: virgin olive oil containing 124 ppm of phenolic compounds and 86 ppm of triterpenes; OVOO enriched with triterpenes (490 ppm of phenolic compounds and 86 ppm of triterpenes); or OVOO without most phenolic compounds Fasting plasma TAG concentrations increased after the virgin olive oil and OVOO interventions. Noteworthy, plasma TAGs were low at baseline (78 ± 5 mg/dL) Sun et al (2018)68 Human 20 healthy Chinese men. Randomized, controlled, single-blinded crossover study. Participants consumed 6 isocaloric meals containing 40 g of SFAs (butter), MUFAs (olive oil), or PUFAs (grapeseed oil) and 50 g of either low-glycemic index (basmati rice) or high-glycemic index (jasmine rice) carbohydrate Serum TAG concentrations increased postprandially Jackson et al (2002)69 Human 9 healthy postmenopausal women. Single-blind randomized within-subject crossover study. Participants consumed 1 of 4 test meals (40 g fat) containing oils with different fatty acid composition: palm oil, rich in SFAs; safflower oil, rich in n-6 PUFAs; 1:1 (vol/vol) mixture of deodorized highly purified fish oil and safflower oil, rich in long-chain PUFAs; and olive oil, rich in n-9 MUFAs Olive oil resulted in an increased apolipoprotein B-48 response compared with the other dietary oils following sequential test meals Perez-Jimenez et al (1995)70 Human 21 healthy, normolipidemic, young males. Volunteers consumed an NCEP-I diet (30% of energy as fat) during a 25-d period. Individuals were then assigned to two 4-wk study periods, according to a randomized, crossover design. Group 1 consumed an olive oil–enriched diet (40% fat, 22% MUFAs) for 4 wk, followed by a sunflower oil–enriched diet (40% fat, 22% MUFAs) for 4 wk. Group 2 consumed these diets in the reverse order The olive oil diet resulted in increased TC, LDL-C, HDL-C, and apolipoprotein A-I compared with the NCEP-I diet Abbreviations: EVOO, extra virgin olive oil; HCD, high-cholesterol diet; HDL-C, high-density lipoprotein cholesterol; HFD, high-fat diet; LDL-C, low-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; NCEP-1, National Cholesterol Education Program 1; Otsuka Long-Evans Tokushima Fatty; OVOO, optimized virgin olive oil high in phenolic compounds; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; TAG, triglycerides; TC, total cholesterol; VLDL-C, very low-density lipoprotein cholesterol. Open in new tab Table 2 Potential adverse effects of olive oil on lipid metabolism in animal and human studies Reference . Species . Model/intervention . Potential adverse effects . Arbones-Mainar et al (2007)41 Mouse 24 female Apoe−/− mice. Standard mouse chow supplemented with 0.15% (wt/wt) cholesterol and 1 of the following: 20% (wt/wt) Picual EVOO (90 mg of (poly)phenols/kg), 20% (wt/wt) Arbequina EVOO (25 mg of (poly)phenols/kg), or 20% (wt/wt) palm oil Olive oil increased both hepatic fat content and adipophilin levels, though Picual olive oil decreased plasma TAGs Ferramosca et al (2008)42 Mouse 50 male ICR mice. Fed for 8 wk with standard diet supplemented with 7.5% olive oil or 7.5% corn oil ↑Hepatic TAGs, TC, and phospholipids in olive oil-fed animals in the eighth week compared to baseline Thuy et al (2001)43 Mouse Male C3H/He mice. Fed for 50 wk with olive oil, safflower oil, or linseed oil diet Plasmatic and hepatic TC and TAGs were increased in the olive oil group Oliván et al (2014)44 Mouse SOD1G93A mice. 3 experimental groups: standard chow diet; chow diet enriched with 20% (wt/wt) EVOO; and chow diet containing 20% palm oil. Fed for 8 wk Compared with controls, mice receiving the high-fat diets showed increased plasma cholesterol levels Acín et al (2007)45 Mouse 26 apoE-deficient mice. Fed chow diet, diet supplemented with standard olive oil devoid of phenolic compounds, or diet supplemented with test olive oil enriched with linoleic acid, phytosterols, tocopherols, triterpenes, and waxes for 11 wk Plasma TC and LDL-C levels increased in mice fed a diet supplemented with standard olive oil Liao et al (2010)46 Hamster Male Golden Syrian hamsters. Randomly assigned to control or obesity groups for 4 wk (period for HFD-induced obesity). For another 8 wk, controls were fed a low-fat diet, but obese mice were switched to a low-fat diet and subdivided into an obesity-control group, a high-MUFA oil with a high ratio of polyunsaturated to saturated fats group, and an olive oil group The olive oil group had significantly increased plasma TC levels compared with the control group and the obesity control group and the highest plasma HDL-C levels among all groups after 8 wk Djohan et al (2019)47 Rat 32 young male Wistar rats. Four groups: 1 was fed control diet (11% energy from fat) and 3 were fed high-fat diets rich in crude or refined palm oils or in olive oil (56% energy from fat) for 12 wk Rats fed the olive oil diet showed hepatic TAG accumulation, inflammation, and cytolysis Duavy et al (2017)48 Rat 15 male Wistar rats (300 g). For 60 d, animals were fed 4% cholesterol-free soybean oil; 1% HCD + 12% oleic acid–rich olive oil; or 1% HCD+12% linoleic acid–rich sunflower oil Rats fed HCD + olive oil showed a decrease in serum LDL-C, VLDL-C, and TC levels compared with rats fed HCD + sunflower oil. However, rats fed HCD + olive oil showed microvesicular steatosis in the hepatic acinar zone 1 Macri et al (2015)49 Rat 80 male weanling Wistar rats. Diets were rich in MUFA oils and contained 20 g of fat per 100 g of diet: AIN-93G (control diet); EVOO + control diet; high-oleic sunflower oil + control diet; or atherogenic diet for 8 wk; the remaining 2 groups received the atherogenic diet for 3 wk, and then the saturated fat was replaced by an oil mixture of soybean oil plus olive oil or high-oleic sunflower oil for 5 wk Rats consuming MUFA-rich diets after the atherogenic diet showed the highest hepatic index and the highest body fat, epididymal fat, intestinal fat, and perirenal fat Ruiz-Gutiérrez et al (2001)50 Rat 40 spontaneously hypertensive rats. Each group was fed 1 of the following diets for 12 wk: a basal diet (control) or the basal diet supplemented with 10% (wt/wt) olive oil, 10% (wt/wt) high-oleic sunflower oil, or 10% (wt/wt) fish oil Compared with controls, olive oil diet led to increases in plasma and hepatic TAGs, TC, and phospholipids Buettner et al (2013)51 Rat Male Wistar rats. Rats (n = 5/group) were fed for 8 wk with standard rodent chow (fat content, 11% energy); atherogenic diet containing 15% neutral fat, 1.25% cholesterol, and 0.5% cholate by mass; atherogenic diet without cholesterol; atherogenic diet without choline; atherogenic diet without cholate; atherogenic diet with olive oil, or atherogenic diet with coconut oil After 8 wk, rats fed the atherogenic diet plus olive oil showed increased TAG levels compared with rats fed the atherogenic diet Adamopoulos et al (1996)52 Rat Male Wistar albino rats. 4 groups of 10 rats each were fed for 40 d. Control group received a nonpurified diet; other 3 groups received the nonpurified diet enriched with fat (14 g fat/100 g diet): egg yolk, olive oil, or safflower oil Olive oil group showed increased TC and TAG levels compared with controls Katsarou et al (2015)53 Rat 64 male Wistar rats. One group was fed an HCD (2 g cholesterol), while 5 other groups were fed a diet supplemented with 10% oils or oil products: HCD + EVOO; HCD + sunflower oil; HCD + high-oleic sunflower oil; HCD + phenolic-deprived EVOO; HCD + sunflower oil enriched with EVOO phenolics; or HCD + high-oleic sunflower oil enriched with EVOO phenolics Groups receiving EVOO, phenolic-deprived EVOO, high-oleic sunflower oil, or high-oleic sunflower oil enriched with EVOO phenolics showed increased serum TC and LDL-C compared with cholesterol-fed group Dulloo et al (1995)54 Rat 48 Sprague-Dawley male rats. Refeeding for 10 d after a 2-wk period of low food intake consisting of a low-fat diet or HFDs that varied in type of fat: lard; coconut oil; olive oil; safflower oil; fish oil; or mixed fats Plasma cholesterol increased in groups fed the HFD + olive oil or the HFD + lard compared with group fed the low-fat diet Jeffery et al (1996)55 Rat Weanling male Lewis rats. Rats fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control Olive oil diet resulted in increased serum TAGs compared with low-fat diet or safflower oil diets. HFD resulted in increased serum TC with HFD Oladapo et al (2017)56 Rat 30 male diabetic Wistar rats. 8-wk intervention with different oils. 5 groups: control diet; diabetic control diet; 10% palm oil–enriched diet; 10% soya oil–enriched diet; or 10% olive oil–enriched diet The group fed olive oil had the highest level of TC and non-HDL-C, the lowest level of HDL-C, and the highest atherogenic index Sasase et al (2007)57 Rat Spontaneously Diabetic Torii rats. Olive oil was administrated orally at 5 mL/kg in a fat absorption test. Blood samples were collected at 0 h, 3 h, and 6 h Elevation of TAGs in plasma and lymph chylomicron was increased in Spontaneously Diabetic Torii rats Deng et al (2004)58 Rat Male hyperinsulinemic corpulent JCR:LA-cp rats. 3 groups, each with 3 obese rats and 3 lean rats, were fed 1 of the following: a control diet (10% of calories from olive oil), an olive oil–enriched diet (40% of calories from olive oil), or a fish oil–enriched diet (40% of calories from menhaden oil) for 2 wk Plasma TAGs were increased in corpulent rats fed the olive oil diet compared with corpulent control rats Mori et al (1997)59 Rat Male OLETF rats (model of spontaneous noninsulin-dependent diabetes mellitus) assigned to 1 of 5 groups of 12 rats each: lard; olive oil; safflower oil; eicosapentaenoic acid ethyl ester (each fed at a daily dose of 0.3 g/kg); or distilled water (controls, 0.3 mL/kg/d) for 17 or 18 wk Increased TAG content in plasma, muscle, and liver in the olive oil group compared with the control group. Increased TC, phospholipids, and free fatty acid levels in olive oil–treated rats compared with control rats Maki et al (2015)60 Human 54 men and women with hypercholesterolemia. Double-blind, randomized, crossover design. 4 tablespoons (≈ 54 g) of corn oil (528 mg phytosterols, 29.7 g PUFAs) or EVOO (120 mg phytosterols, 5.6 g PUFAs) per day was provided in 3 servings of study product per day as part of a weight maintenance diet TAG concentrations increased from baseline in both groups, especially in the EVOO group (13.0% increase), although statistical significance was not reported Vogel et al (2000)61 Human 10 healthy, normolipidemic individuals. 3 meals with different sources of fat added: EVOO (50 g), canola oil (50 g), or canned red salmon; and 2 meals containing olive oil and antioxidant vitamins and foods Mean serum TAGs increased after each meal. The EVOO meal with no added foods or vitamins decreased endothelial function postprandially Abia et al (1999)62 Human 8 healthy normolipidemic individuals. Participants ingested a meal rich in virgin olive oil (70 g). Fasting (0 h) and postprandial blood samples were collected hourly for 7 h Plasma and lipoprotein TAG concentrations increased quickly over fasting values and peaked twice at 2 h and 6 h during the 7-h postprandial period Fitó et al (2002)63 Human 16 healthy volunteers. Participants ingested 50 mL of virgin olive oil in a single dose. Blood samples were collected from 0 to 24 h Serum TAG, plasma fatty acids, and lipid peroxidation products increased in plasma and VLDL-C, reaching a peak at 4–6 h and returning to baseline values at 24 h Rueda-Clausen et al (2007)64 Human 10 healthy young men. Participants were randomly assigned to receive 60 mL of soybean, olive, or palm oil, administered once weekly in a soup meal for 9 wk All meals resulted in a similar postprandial increase in TAGs, independent of the type of oil consumed Stonehouse et al (2015)65 Human 28 overweight/obese men. Volunteers consumed, in random order 1 wk apart, isocaloric high-protein, high-fat meals prepared with either 40 g of palmolein or 40 g of olive oil after an overnight fast Postprandial serum TAG concentrations increased Tholstrup et al (2011)66 Human 10 healthy women. Randomized, crossover, postprandial study. Volunteers consumed test meals containing 1 g of fat per kilogram of body weight (mean intake, 62 g). Meals prepared with either cocoa butter high in stearic acid or olive oil Both meals resulted in a significant increase in serum TAG concentrations over time Sanchez-Rodriguez et al (2018)67 Human 58 healthy individuals. 3-wk randomized, crossover, controlled, double-blind, intervention study. Participants received a daily dose (30 mL) of the following: virgin olive oil containing 124 ppm of phenolic compounds and 86 ppm of triterpenes; OVOO enriched with triterpenes (490 ppm of phenolic compounds and 86 ppm of triterpenes); or OVOO without most phenolic compounds Fasting plasma TAG concentrations increased after the virgin olive oil and OVOO interventions. Noteworthy, plasma TAGs were low at baseline (78 ± 5 mg/dL) Sun et al (2018)68 Human 20 healthy Chinese men. Randomized, controlled, single-blinded crossover study. Participants consumed 6 isocaloric meals containing 40 g of SFAs (butter), MUFAs (olive oil), or PUFAs (grapeseed oil) and 50 g of either low-glycemic index (basmati rice) or high-glycemic index (jasmine rice) carbohydrate Serum TAG concentrations increased postprandially Jackson et al (2002)69 Human 9 healthy postmenopausal women. Single-blind randomized within-subject crossover study. Participants consumed 1 of 4 test meals (40 g fat) containing oils with different fatty acid composition: palm oil, rich in SFAs; safflower oil, rich in n-6 PUFAs; 1:1 (vol/vol) mixture of deodorized highly purified fish oil and safflower oil, rich in long-chain PUFAs; and olive oil, rich in n-9 MUFAs Olive oil resulted in an increased apolipoprotein B-48 response compared with the other dietary oils following sequential test meals Perez-Jimenez et al (1995)70 Human 21 healthy, normolipidemic, young males. Volunteers consumed an NCEP-I diet (30% of energy as fat) during a 25-d period. Individuals were then assigned to two 4-wk study periods, according to a randomized, crossover design. Group 1 consumed an olive oil–enriched diet (40% fat, 22% MUFAs) for 4 wk, followed by a sunflower oil–enriched diet (40% fat, 22% MUFAs) for 4 wk. Group 2 consumed these diets in the reverse order The olive oil diet resulted in increased TC, LDL-C, HDL-C, and apolipoprotein A-I compared with the NCEP-I diet Reference . Species . Model/intervention . Potential adverse effects . Arbones-Mainar et al (2007)41 Mouse 24 female Apoe−/− mice. Standard mouse chow supplemented with 0.15% (wt/wt) cholesterol and 1 of the following: 20% (wt/wt) Picual EVOO (90 mg of (poly)phenols/kg), 20% (wt/wt) Arbequina EVOO (25 mg of (poly)phenols/kg), or 20% (wt/wt) palm oil Olive oil increased both hepatic fat content and adipophilin levels, though Picual olive oil decreased plasma TAGs Ferramosca et al (2008)42 Mouse 50 male ICR mice. Fed for 8 wk with standard diet supplemented with 7.5% olive oil or 7.5% corn oil ↑Hepatic TAGs, TC, and phospholipids in olive oil-fed animals in the eighth week compared to baseline Thuy et al (2001)43 Mouse Male C3H/He mice. Fed for 50 wk with olive oil, safflower oil, or linseed oil diet Plasmatic and hepatic TC and TAGs were increased in the olive oil group Oliván et al (2014)44 Mouse SOD1G93A mice. 3 experimental groups: standard chow diet; chow diet enriched with 20% (wt/wt) EVOO; and chow diet containing 20% palm oil. Fed for 8 wk Compared with controls, mice receiving the high-fat diets showed increased plasma cholesterol levels Acín et al (2007)45 Mouse 26 apoE-deficient mice. Fed chow diet, diet supplemented with standard olive oil devoid of phenolic compounds, or diet supplemented with test olive oil enriched with linoleic acid, phytosterols, tocopherols, triterpenes, and waxes for 11 wk Plasma TC and LDL-C levels increased in mice fed a diet supplemented with standard olive oil Liao et al (2010)46 Hamster Male Golden Syrian hamsters. Randomly assigned to control or obesity groups for 4 wk (period for HFD-induced obesity). For another 8 wk, controls were fed a low-fat diet, but obese mice were switched to a low-fat diet and subdivided into an obesity-control group, a high-MUFA oil with a high ratio of polyunsaturated to saturated fats group, and an olive oil group The olive oil group had significantly increased plasma TC levels compared with the control group and the obesity control group and the highest plasma HDL-C levels among all groups after 8 wk Djohan et al (2019)47 Rat 32 young male Wistar rats. Four groups: 1 was fed control diet (11% energy from fat) and 3 were fed high-fat diets rich in crude or refined palm oils or in olive oil (56% energy from fat) for 12 wk Rats fed the olive oil diet showed hepatic TAG accumulation, inflammation, and cytolysis Duavy et al (2017)48 Rat 15 male Wistar rats (300 g). For 60 d, animals were fed 4% cholesterol-free soybean oil; 1% HCD + 12% oleic acid–rich olive oil; or 1% HCD+12% linoleic acid–rich sunflower oil Rats fed HCD + olive oil showed a decrease in serum LDL-C, VLDL-C, and TC levels compared with rats fed HCD + sunflower oil. However, rats fed HCD + olive oil showed microvesicular steatosis in the hepatic acinar zone 1 Macri et al (2015)49 Rat 80 male weanling Wistar rats. Diets were rich in MUFA oils and contained 20 g of fat per 100 g of diet: AIN-93G (control diet); EVOO + control diet; high-oleic sunflower oil + control diet; or atherogenic diet for 8 wk; the remaining 2 groups received the atherogenic diet for 3 wk, and then the saturated fat was replaced by an oil mixture of soybean oil plus olive oil or high-oleic sunflower oil for 5 wk Rats consuming MUFA-rich diets after the atherogenic diet showed the highest hepatic index and the highest body fat, epididymal fat, intestinal fat, and perirenal fat Ruiz-Gutiérrez et al (2001)50 Rat 40 spontaneously hypertensive rats. Each group was fed 1 of the following diets for 12 wk: a basal diet (control) or the basal diet supplemented with 10% (wt/wt) olive oil, 10% (wt/wt) high-oleic sunflower oil, or 10% (wt/wt) fish oil Compared with controls, olive oil diet led to increases in plasma and hepatic TAGs, TC, and phospholipids Buettner et al (2013)51 Rat Male Wistar rats. Rats (n = 5/group) were fed for 8 wk with standard rodent chow (fat content, 11% energy); atherogenic diet containing 15% neutral fat, 1.25% cholesterol, and 0.5% cholate by mass; atherogenic diet without cholesterol; atherogenic diet without choline; atherogenic diet without cholate; atherogenic diet with olive oil, or atherogenic diet with coconut oil After 8 wk, rats fed the atherogenic diet plus olive oil showed increased TAG levels compared with rats fed the atherogenic diet Adamopoulos et al (1996)52 Rat Male Wistar albino rats. 4 groups of 10 rats each were fed for 40 d. Control group received a nonpurified diet; other 3 groups received the nonpurified diet enriched with fat (14 g fat/100 g diet): egg yolk, olive oil, or safflower oil Olive oil group showed increased TC and TAG levels compared with controls Katsarou et al (2015)53 Rat 64 male Wistar rats. One group was fed an HCD (2 g cholesterol), while 5 other groups were fed a diet supplemented with 10% oils or oil products: HCD + EVOO; HCD + sunflower oil; HCD + high-oleic sunflower oil; HCD + phenolic-deprived EVOO; HCD + sunflower oil enriched with EVOO phenolics; or HCD + high-oleic sunflower oil enriched with EVOO phenolics Groups receiving EVOO, phenolic-deprived EVOO, high-oleic sunflower oil, or high-oleic sunflower oil enriched with EVOO phenolics showed increased serum TC and LDL-C compared with cholesterol-fed group Dulloo et al (1995)54 Rat 48 Sprague-Dawley male rats. Refeeding for 10 d after a 2-wk period of low food intake consisting of a low-fat diet or HFDs that varied in type of fat: lard; coconut oil; olive oil; safflower oil; fish oil; or mixed fats Plasma cholesterol increased in groups fed the HFD + olive oil or the HFD + lard compared with group fed the low-fat diet Jeffery et al (1996)55 Rat Weanling male Lewis rats. Rats fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control Olive oil diet resulted in increased serum TAGs compared with low-fat diet or safflower oil diets. HFD resulted in increased serum TC with HFD Oladapo et al (2017)56 Rat 30 male diabetic Wistar rats. 8-wk intervention with different oils. 5 groups: control diet; diabetic control diet; 10% palm oil–enriched diet; 10% soya oil–enriched diet; or 10% olive oil–enriched diet The group fed olive oil had the highest level of TC and non-HDL-C, the lowest level of HDL-C, and the highest atherogenic index Sasase et al (2007)57 Rat Spontaneously Diabetic Torii rats. Olive oil was administrated orally at 5 mL/kg in a fat absorption test. Blood samples were collected at 0 h, 3 h, and 6 h Elevation of TAGs in plasma and lymph chylomicron was increased in Spontaneously Diabetic Torii rats Deng et al (2004)58 Rat Male hyperinsulinemic corpulent JCR:LA-cp rats. 3 groups, each with 3 obese rats and 3 lean rats, were fed 1 of the following: a control diet (10% of calories from olive oil), an olive oil–enriched diet (40% of calories from olive oil), or a fish oil–enriched diet (40% of calories from menhaden oil) for 2 wk Plasma TAGs were increased in corpulent rats fed the olive oil diet compared with corpulent control rats Mori et al (1997)59 Rat Male OLETF rats (model of spontaneous noninsulin-dependent diabetes mellitus) assigned to 1 of 5 groups of 12 rats each: lard; olive oil; safflower oil; eicosapentaenoic acid ethyl ester (each fed at a daily dose of 0.3 g/kg); or distilled water (controls, 0.3 mL/kg/d) for 17 or 18 wk Increased TAG content in plasma, muscle, and liver in the olive oil group compared with the control group. Increased TC, phospholipids, and free fatty acid levels in olive oil–treated rats compared with control rats Maki et al (2015)60 Human 54 men and women with hypercholesterolemia. Double-blind, randomized, crossover design. 4 tablespoons (≈ 54 g) of corn oil (528 mg phytosterols, 29.7 g PUFAs) or EVOO (120 mg phytosterols, 5.6 g PUFAs) per day was provided in 3 servings of study product per day as part of a weight maintenance diet TAG concentrations increased from baseline in both groups, especially in the EVOO group (13.0% increase), although statistical significance was not reported Vogel et al (2000)61 Human 10 healthy, normolipidemic individuals. 3 meals with different sources of fat added: EVOO (50 g), canola oil (50 g), or canned red salmon; and 2 meals containing olive oil and antioxidant vitamins and foods Mean serum TAGs increased after each meal. The EVOO meal with no added foods or vitamins decreased endothelial function postprandially Abia et al (1999)62 Human 8 healthy normolipidemic individuals. Participants ingested a meal rich in virgin olive oil (70 g). Fasting (0 h) and postprandial blood samples were collected hourly for 7 h Plasma and lipoprotein TAG concentrations increased quickly over fasting values and peaked twice at 2 h and 6 h during the 7-h postprandial period Fitó et al (2002)63 Human 16 healthy volunteers. Participants ingested 50 mL of virgin olive oil in a single dose. Blood samples were collected from 0 to 24 h Serum TAG, plasma fatty acids, and lipid peroxidation products increased in plasma and VLDL-C, reaching a peak at 4–6 h and returning to baseline values at 24 h Rueda-Clausen et al (2007)64 Human 10 healthy young men. Participants were randomly assigned to receive 60 mL of soybean, olive, or palm oil, administered once weekly in a soup meal for 9 wk All meals resulted in a similar postprandial increase in TAGs, independent of the type of oil consumed Stonehouse et al (2015)65 Human 28 overweight/obese men. Volunteers consumed, in random order 1 wk apart, isocaloric high-protein, high-fat meals prepared with either 40 g of palmolein or 40 g of olive oil after an overnight fast Postprandial serum TAG concentrations increased Tholstrup et al (2011)66 Human 10 healthy women. Randomized, crossover, postprandial study. Volunteers consumed test meals containing 1 g of fat per kilogram of body weight (mean intake, 62 g). Meals prepared with either cocoa butter high in stearic acid or olive oil Both meals resulted in a significant increase in serum TAG concentrations over time Sanchez-Rodriguez et al (2018)67 Human 58 healthy individuals. 3-wk randomized, crossover, controlled, double-blind, intervention study. Participants received a daily dose (30 mL) of the following: virgin olive oil containing 124 ppm of phenolic compounds and 86 ppm of triterpenes; OVOO enriched with triterpenes (490 ppm of phenolic compounds and 86 ppm of triterpenes); or OVOO without most phenolic compounds Fasting plasma TAG concentrations increased after the virgin olive oil and OVOO interventions. Noteworthy, plasma TAGs were low at baseline (78 ± 5 mg/dL) Sun et al (2018)68 Human 20 healthy Chinese men. Randomized, controlled, single-blinded crossover study. Participants consumed 6 isocaloric meals containing 40 g of SFAs (butter), MUFAs (olive oil), or PUFAs (grapeseed oil) and 50 g of either low-glycemic index (basmati rice) or high-glycemic index (jasmine rice) carbohydrate Serum TAG concentrations increased postprandially Jackson et al (2002)69 Human 9 healthy postmenopausal women. Single-blind randomized within-subject crossover study. Participants consumed 1 of 4 test meals (40 g fat) containing oils with different fatty acid composition: palm oil, rich in SFAs; safflower oil, rich in n-6 PUFAs; 1:1 (vol/vol) mixture of deodorized highly purified fish oil and safflower oil, rich in long-chain PUFAs; and olive oil, rich in n-9 MUFAs Olive oil resulted in an increased apolipoprotein B-48 response compared with the other dietary oils following sequential test meals Perez-Jimenez et al (1995)70 Human 21 healthy, normolipidemic, young males. Volunteers consumed an NCEP-I diet (30% of energy as fat) during a 25-d period. Individuals were then assigned to two 4-wk study periods, according to a randomized, crossover design. Group 1 consumed an olive oil–enriched diet (40% fat, 22% MUFAs) for 4 wk, followed by a sunflower oil–enriched diet (40% fat, 22% MUFAs) for 4 wk. Group 2 consumed these diets in the reverse order The olive oil diet resulted in increased TC, LDL-C, HDL-C, and apolipoprotein A-I compared with the NCEP-I diet Abbreviations: EVOO, extra virgin olive oil; HCD, high-cholesterol diet; HDL-C, high-density lipoprotein cholesterol; HFD, high-fat diet; LDL-C, low-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; NCEP-1, National Cholesterol Education Program 1; Otsuka Long-Evans Tokushima Fatty; OVOO, optimized virgin olive oil high in phenolic compounds; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; TAG, triglycerides; TC, total cholesterol; VLDL-C, very low-density lipoprotein cholesterol. Open in new tab RODENT MODELS The liver regulates lipid metabolism by modulating lipogenesis, cholesterol synthesis and uptake, response to nutritional challenges, etc.71 Hepatic accumulation of TAGs is linked to disorders such as steatosis, liver inflammation and fibrosis, and insulin resistance.72,73 Although basic molecular mechanisms of the biosynthesis, uptake, and clearance of cholesterol and lipids are conserved in most mammals, systemic differences in lipid metabolism between species highlight the need for appropriate animal models when investigating lipid metabolism.74 There are major differences between plasma lipoproteins in humans and those in rodents, the most widely used animal model75 (Figure 1).39,40,56,77–83 Increased hepatic steatosis following consumption of olive oil–rich diets has been reported in rodent studies. For instance, consumption of an olive oil diet (20% wt/wt) for 4 weeks led to a significant increase in hepatic TAG levels as well as increased activity of some liver lipogenic enzymes when compared with consumption of a palm oil diet (20% wt/wt).76 Moreover, a 10-week olive oil–rich diet (20% wt/wt) resulted in higher levels of hepatic fat accumulation compared with a palm oil–rich diet.41 In addition, mice fed an olive oil–enriched diet for 8 weeks exhibited higher liver TAG levels compared with mice fed a corn oil–enriched diet, although no increase in cytosolic lipogenic enzyme activity was observed.42 In young male Wistar rats, a high dietary intake of olive oil (56% energy from fat) resulted in hepatic TAG accumulation, inflammation, and cytolysis.47 In another study, rats were fed for 60 days with a 4% cholesterol-free soybean oil diet; a 1% high-cholesterol diet plus 12% oleic acid–rich olive oil enriched with MUFAs; or a 1% high-cholesterol diet plus 12% linoleic acid–rich sunflower oil enriched with PUFAs. Both the high-cholesterol diet plus olive oil and the high-cholesterol diet plus 12% linoleic acid–rich sunflower oil resulted in the onset of microvesicular steatosis, which was most severe in the former group (affecting mainly the hepatic acinar zone 1).48 In the study by Macri et al,49 3 groups of rats received an atherogenic diet (20 g fat/100 g of diet, rich in saturated fatty acids [12.3%] and cholesterol [4%]) for 3 weeks. Over the next 5 weeks, 1 group continued the atherogenic diet, but the other 2 groups were fed a diet in which the source of saturated fat was replaced by 7% soybean oil plus 13% olive oil or high-oleic sunflower oil. Rats consuming MUFA-rich diets after the initial atherogenic diet had the highest amounts of epididymal, intestinal, and perirenal fat and the highest hepatic index.49 In another study, spontaneously hypertensive rats fed a standard diet supplemented with 10% olive oil for 12 weeks presented higher plasma and hepatic TAGs, higher total cholesterol (TC), and higher phospholipids compared with animals fed a basal diet alone.50 In an 8-week study, rats were fed an atherogenic diet (composed of 15% neutral fat, 1.25% cholesterol, and 0.5% cholate by mass); an atherogenic diet without cholesterol; an atherogenic diet without choline; an atherogenic diet without cholate; an atherogenic diet with olive oil; or an atherogenic diet with coconut oil. The atherogenic diet with olive oil attenuated hepatic inflammation, but fat deposition and features of the metabolic syndrome were increased.51 A study in male C3H/He mice fed diets containing olive oil, safflower oil, or linseed oil for 50 weeks found that plasmatic and hepatic TC and TAGs were higher in the mice fed olive oil.43 Figure 1 Open in new tabDownload slide Systemic differences in lipid metabolism between humans and rodent models. Although basic molecular mechanisms involved in the biosynthesis, uptake, and clearance of cholesterol and lipids are conserved in most mammals, systemic differences in lipid metabolism between species highlight the need for appropriate animal models when investigating lipid metabolism.39 Rodents, the most widely used type of animal model, are profoundly different from humans in terms of plasma lipoproteins.40 Mice are more resistant than humans to cardiovascular disease, and approximately 80% of serum cholesterol is in the HDLc fraction in mice; in normolipidemic humans, this value is 20% to 30%. In addition, rodents exhibit low levels of ApoB-containing lipoproteins77 and lack CETP.78 Another difference is that, in humans, ApoB-48 is synthesized by the intestine and is essential for the assembly of chylomicrons, while in mice, ApoB-48 is produced preferentially by the liver. Furthermore, although ApoB-100 is produced by the liver and is required for the synthesis and secretion of VLDLc (metabolized into LDLc) in humans, ApoB-48 accounts for up to 50% of circulating ApoB in rodents. Thus, these and other genetic diversities may account for the differences in lipid metabolism observed when comparing mice and human studies. In recent years, more appropriate models have been developed to study lipid metabolism in the context of basal dyslipidemia and diet-induced dyslipidemia. These so-called humanized mice exhibit an altered distribution of lipoproteins that more closely resembles the distribution of cholesterol in normolipidemic humans. Examples include transgenic mice expressing CETP,78,79 human ApoB,80,81 human ApoA-I,82 or other knockout models such as LDLR, ApoE, ApoA-I, Apobec-1, and their combinations.39,56,83 In summary, compared with wild-type mice, humanized mice might be a more useful model to study the effects of overconsumption of olive oil on lipid metabolism. Abbreviations: ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; Apobec-1, apolipoprotein B editing complex 1; ApoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; VLDLc, very low-density lipoprotein cholesterol. Figure 1 Open in new tabDownload slide Systemic differences in lipid metabolism between humans and rodent models. Although basic molecular mechanisms involved in the biosynthesis, uptake, and clearance of cholesterol and lipids are conserved in most mammals, systemic differences in lipid metabolism between species highlight the need for appropriate animal models when investigating lipid metabolism.39 Rodents, the most widely used type of animal model, are profoundly different from humans in terms of plasma lipoproteins.40 Mice are more resistant than humans to cardiovascular disease, and approximately 80% of serum cholesterol is in the HDLc fraction in mice; in normolipidemic humans, this value is 20% to 30%. In addition, rodents exhibit low levels of ApoB-containing lipoproteins77 and lack CETP.78 Another difference is that, in humans, ApoB-48 is synthesized by the intestine and is essential for the assembly of chylomicrons, while in mice, ApoB-48 is produced preferentially by the liver. Furthermore, although ApoB-100 is produced by the liver and is required for the synthesis and secretion of VLDLc (metabolized into LDLc) in humans, ApoB-48 accounts for up to 50% of circulating ApoB in rodents. Thus, these and other genetic diversities may account for the differences in lipid metabolism observed when comparing mice and human studies. In recent years, more appropriate models have been developed to study lipid metabolism in the context of basal dyslipidemia and diet-induced dyslipidemia. These so-called humanized mice exhibit an altered distribution of lipoproteins that more closely resembles the distribution of cholesterol in normolipidemic humans. Examples include transgenic mice expressing CETP,78,79 human ApoB,80,81 human ApoA-I,82 or other knockout models such as LDLR, ApoE, ApoA-I, Apobec-1, and their combinations.39,56,83 In summary, compared with wild-type mice, humanized mice might be a more useful model to study the effects of overconsumption of olive oil on lipid metabolism. Abbreviations: ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; Apobec-1, apolipoprotein B editing complex 1; ApoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; VLDLc, very low-density lipoprotein cholesterol. Other studies have reported abnormal levels of circulating lipid parameters following chronic consumption of olive oil–supplemented diets. For example, in rats fed for 40 days with a control diet alone or a control diet enriched with egg yolk, safflower oil, or olive oil to provide 14 g fat/100 g of diet, plasma TC and TAG levels were higher in the olive oil group than in the control group.52 In a study by Katsarou et al,53 rats were fed a standard diet (control) or a high-cholesterol (2 g) diet plus a 10% supplementation with one of the following: sunflower oil; sunflower oil enriched with EVOO phenolics; EVOO; phenolic-deprived EVOO; high-oleic sunflower oil; or high-oleic sunflower oil enriched with EVOO phenolics. The last 4 diets resulted in higher levels of serum TC and low-density lipoprotein cholesterol (LDL-C) compared with both control groups.53 In another study, Sprague-Dawley male rats were subjected to a 2-week period of low food intake followed by refeeding for 10 days with either a low-fat diet or a high-fat diet containing different types of fat: lard; coconut oil; olive oil; safflower oil; fish oil; or mixed types of fats.54 At day 10, both the high-fat diet plus olive oil group and the high-fat diet plus lard group showed higher plasma TC compared with the low-fat diet group.54 SOD1G93A mice fed a standard chow diet enriched with 20% (wt/wt) EVOO or 20% palm oil for 8 weeks showed higher plasma TC levels than mice fed a standard chow diet alone.44 In an 8-week study, lean male Golden Syrian hamsters were fed a low-fat diet (lean controls), while obese hamsters were fed a low-fat diet alone (obesity controls), a low-fat diet supplemented with a high-MUFA oil (high ratio of polyunsaturated to saturated fats), or olive oil.46 The olive oil group had significantly higher plasma TC levels than both lean and obese controls and the highest plasma levels of high-density lipoprotein cholesterol (HDL-C) among all groups. Acín et al45 observed that plasma TC and LDL-C levels were higher in apolipoprotein E–deficient mice fed a diet supplemented with a standard olive oil devoid of phenolic compounds than in mice fed either a standard chow diet or a diet containing olive oil enriched with linoleic acid, phytosterols, tocopherols, triterpenes, and waxes, supporting the notion that the beneficial properties of olive oil derive from phenolic compounds. It must be underscored that almost all of the aforementioned studies were performed with extremely high doses of oils and fats, far exceeding any international recommendation. Therefore, the relevance of those data to human nutrition must be assessed with caution. Moreover, the adverse effects on hepatic parameters and the abnormal levels of circulating lipid markers reported in those studies may not be transferable to humans because of the metabolic differences between rodents and humans. Finally, the amount of fat in the average quantity of olive oil ingested by the population is low compared with the total amount of fat in a high-fat diet. HUMAN STUDIES Several clinical trials have been carried out to evaluate the effects of phenolic-rich olive oils in humans. These include the Virgin Olive Oil Study (VOLOS),84 the Spanish Olive Oil Study (SOLOS),85,86 the EUROLIVE study,87–89 the PREDIMED study,90 and the Virgin Olive Oil and HDL Functionality (VOHF) study.91,92 A positive correlation between the intake of phenolic-rich olive oils and the improvement in levels of circulating lipid markers, involving a decrease in oxidized LDL-C, TAGs, and TC and an increase in HDL-C, was reported by some, but not all studies. 60,93–97 In the case of HDL-C, which is largely responsible for removing excess cholesterol from tissues and carrying it back to the liver for clearance (the reverse cholesterol transport),98 recent studies highlight the intricacy of the relationship between circulating concentrations of HDL-C and coronary artery disease.99 In this sense, the absolute amount of circulating HDL-C might not be as important as how efficiently HDL-C particles complete reverse cholesterol transport.100 For example, African green monkeys fed a diet rich in monounsaturated fat for 5 years presented similar coronary artery atherosclerosis as those fed saturated fat, even though they had lower LDL-C levels and higher HDL-C levels.101 Cortés et al102 studied the supplementation of olive oil (25 g/d) to 12 healthy and 12 hypercholesterolemic patients following a meal containing 80 g of fat (35% saturated fatty acids). The authors found that olive oil supplementation did not augment flow-mediated dilation (an indicator of endothelial function, impairment of which is associated with high fat consumption) yet increased the ratio of very low-density lipoprotein cholesterol (VLDL-C) TAGs to apolipoprotein B (an indirect indicator of the presence of large TAG-rich VLDL-C particles) when compared with a similar experiment conducted with walnuts.102 Furthermore, in a study investigating vasomotion after meals, a significant impairment of endothelial function was found only after the consumption of a meal rich in olive oil.61 Finally, a study conducted by Sala-Vila et al103 within the frame of the PREDIMED trial demonstrated that daily supplementation with olive oil did not result in regression of internal carotid intima-media thickness or plaque height. (Poly)phenols have been suggested to increase HDL-C concentrations and, probably, efflux capacity,104 Olive oil phenolics act in a similar manner.89 The mechanisms of action responsible for these activities are still unclear and are under investigation.105 Foods and meals that improve postprandial TAG concentrations might improve human health.106 Indeed, excessive levels of TAG-rich lipoproteins during postprandial lipemia have been reported to be atherogenic. Some have suggested that this effect should be considered a clinically important risk factor for cardiovascular disease.107,108 Ingestion of meal rich in VOO (70 g) by healthy normolipidemic study participants resulted in a rapid rise in plasma and lipoprotein TAG concentrations compared with fasting values and peaked twice at 2 hours and 6 hours during a 7-hour postprandial period.52 Serum TAGs, plasma fatty acids, and lipid peroxidation products in plasma and VLDL-C also increased in healthy volunteers who ingested 50 mL of VOO in a single dose, reaching a peak between 4 and 6 hours and returning to baseline values at 24 hours.63 In a study with healthy volunteers, a meal containing 40 g of butter induced a lower postprandial rise in TAGs in serum and chylomicrons than meals containing 40 g of either olive oil or sunflower oil.109 A study in healthy young individuals who ate a potato soup meal containing 60 mL of olive oil, soybean oil, or palm oil reported a similar acute impairment in endothelial function and a postprandial increase in TAGs after 3 hours, independent of the type of oil ingested.64 In a double-blinded, randomized, crossover study, hypercholesterolemic patients consumed 4 tablespoons (≈ 54 g) of corn oil (528 mg phytosterols, 29.7 g PUFAs) or EVOO (120 mg phytosterols, 5.6 g PUFAs) per day, provided in 3 servings of the study products per day as part of a weight maintenance diet. Triglyceride concentrations increased from baseline (statistical significance was not reported) with both diets, especially the EVOO diet (13.0%).60 In another study, postprandial serum TAG concentrations increased significantly, reaching peak concentrations at 4 hours, in overweight/obese men who consumed, in random order and 1 week apart, isocaloric high-protein, high-fat meals prepared with either 40 g of palmolein or 40 g of olive oil after an overnight fast, with no difference in response between meals.65 Moreover, in a randomized, crossover, postprandial study, healthy women consumed test meals containing 1 g of fat per kilogram of body weight (mean, 62 g) prepared with either cocoa butter high in stearic acid or olive oil. Both diets resulted in a significant rise in serum TAGs concentration over time.66 In a 3-week randomized, crossover, controlled, double-blind, intervention study, 58 healthy individuals received a daily dose (30 mL) of VOO (124 ppm of phenolic compounds and 86 ppm of triterpenes); optimized VOO enriched with triterpenes (490 ppm of phenolic compounds and 86 ppm of triterpenes); or optimized VOO without most phenolic compounds.67 Fasting plasma TAG concentrations increased after the VOO and optimized VOO interventions (noteworthy, plasma TAGs were low at baseline, 78 ± 5 mg/dL). In a randomized, controlled, single-blinded crossover study, 20 healthy Chinese men received, in random order, 6 experimental isocaloric meals that differed in carbohydrate and fat quality. Each meal contained 40 g of saturated fat (saturated fatty acids, butter), monounsaturated fat (MUFAs, olive oil), or polyunsaturated fat (PUFAs, grapeseed oil) plus 50 g of either low-glycemic-index carbohydrate (basmati rice) or high-glycemic-index carbohydrate (jasmine rice). A carbohydrate-rich meal (either low or high glycemic index) containing olive oil resulted in higher postprandial TAG concentrations relative to a carbohydrate-rich mean containing butter or grapeseed oil.68 In a single-blind, randomized, within-participant crossover study, 9 healthy postmenopausal women received 4 test meals (each containing 40 g of fat), each with a different fatty acid composition: (1) palm oil, rich in saturated fatty acids; (2) safflower oil, rich in n-6 PUFAs; (3) a 1:1 (vol/vol) mixture of deodorized highly purified fish oil and safflower oil, rich in long-chain PUFAs; and (4) olive oil, rich in n-9 MUFAs.69 After consumption of sequential test meals, olive oil resulted in a significant increase in the apolipoprotein B-48 response compared with the other dietary oils.69 In a randomized crossover study, healthy, normolipidemic young men consumed a National Cholesterol Education Program type I (NCEP-I) diet (30% of energy as fat) during a 25-day period and were then assigned to one of two 4-week study periods.70 Group 1 ate an olive oil–enriched diet (40% fat, 22% MUFAs) for 4 weeks, followed by a sunflower oil–enriched diet (40% fat, 22% MUFAs) for 4 weeks. In group 2, the order of the diets was reversed. The olive oil diet resulted in higher levels of TC, LDL-C, HDL-C, and apolipoprotein A-I compared with the NCEP-I diet.70 In summary, high-fat meals, whether rich in olive oil, corn oil, or any other kind of fat or oil, are to be avoided because they greatly increase caloric intake and impair metabolic flexibility, as discussed below. POTENTIAL ADVERSE EFFECTS OF THE MAIN COMPONENTS OF OLIVE OIL ON LIPID METABOLISM The health effects of olive oil are attributed to the additive actions of all of its components. Nevertheless, a separate analysis of each component can be useful for understanding why too much olive oil might be harmful. Fatty acids As mentioned above, oleic acid is the most plentiful fatty acid in olive oil (constituting ≈ 70% of total fatty acids), followed by palmitic and linoleic acids, respectively. Even though fatty acids are important substrates in metabolic pathways and a source of energy, they can be harmful if consumed in excess, as lipotoxicity can be induced and several inflammatory pathways can be stimulated.110 PubMed and Scopus databases were examined by entering “oleic acid,” “linoleic acid,” or “palmitic acid” and adding keywords such as “lipid metabolism,” “triglycerides,” “cholesterol,” “lipid synthesis,” “lipid profile,” or “lipoproteins.” Papers reporting adverse in vivo effects related to lipid metabolism were critically reviewed and summarized. As mentioned above, oleic acid consumption is generally considered cardioprotective. Indeed, studies in which oleic acid–enriched diets resulted in potential adverse effects on lipid metabolism are scant. Nevertheless, several examples are worth discussing. In weanling rats fed for 6 weeks, diets containing oleic acid–rich olive oil or high-oleic-acid sunflower oil increased both serum TAGs and serum TC concentrations compared with a low-fat diet or a safflower oil diet, leading the authors to suggest that such adverse effects were related to oleic acid.55 In weanling pigs, the main outcome of an oleic acid–enriched diet was a rise in VLDL-C and TC concentrations, almost to the level observed with the myristoleic/palmitoleic acid–enriched diet.111 In a prospective study in healthy infants, dietary fatty acids and TC were monitored for 1 year from birth, and the cholesterol response to a human milk–based diet was compared with the response to diets rich in oleic acid or linoleic acid. In the oleic acid group, LDL-C levels were significantly increased after 12 months compared with levels after 4 months.112 Cholesterol ester fatty acid composition is affected by the type of dietary fat ingested over the previous few weeks113 and may, therefore, be considered representative of dietary fat quality. Oleic acid feeding results in increased content of cholesteryl oleate in LDL-C particles, which is linked to augmented LDL-C–proteoglycan binding and atherosclerosis. Jones et al114 reported a rise in the cholesteryl oleate percentage in LDL-C after high-oleic canola oil ingestion in humans, yet this was not accompanied by a rise in LDL-C–proteoglycan binding. An overview of these studies is provided in Table 3.55,111,112,114–120 Table 3 Potential adverse effects of oleic acid on lipid metabolism in animal and human studies References . Species . Model/intervention . Potential adverse effects . Jeffery et al (1996)55 Rat Weanling male Lewis rats (n ≥ 6 for each diet) were fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic-acid sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control The olive oil and the high-oleic-acid sunflower oil diets both resulted in increased serum TAG compared with the low-fat and the safflower oil diets. Levels of serum TC increased in animals fed the high-fat diets and were highest in animals fed the olive oil or the high-oleic-acid sunflower oil diet Giudetti et al (2003)115 Rat Male Wistar rats were fed cholesterol-free diets containing stearic acid, oleic acid, or elaidic acid (n = 12/group) for 14 d Oleic acid increased the concentration of TAG in the liver compared with stearic acid Smith et al (1996)111 Swine Weanling pigs were fed diets containing added cornstarch (10 g/100 g chow) (to provide baseline data) or added fatty acids (10 g/100 g chow) for 35 d. Diets with added fatty acids contained ≈ 30% myristic acid plus the following: 36% myristoleic acid + palmitoleic acid combined; 52% palmitic acid; 51% stearic acid; 47% oleic acid; or 38% linoleic acid All diets caused a significant increase in TAG, TC, LDL-C, HDL-C, and VLDL-C. The increase in plasma TC from pretreatment values was greatest in pigs fed the myristoleic acid + palmitoleic acid and oleic acid diets. Increases in VLDL-C above pretreatment concentrations were lowest in palmitic acid–fed pigs and greatest in oleic acid–fed pigs Spreafico et al (2018)116 Nonhuman primate 20 common marmosets were fed 2 diets supplemented with either African palm oil or hybrid palm oil for 3 months. Hybrid palm oil had a higher level of oleic acid and a lower level of palmitic acid content than African palm oil Animals fed hybrid palm oil showed increased hepatic total lipid content and circulating transaminases, as well as an increased degree of fibrosis, without any apparent changes in plasma lipid levels or lipoprotein profile Mize et al (1995)112 Human 62 normal newborn infants. 12-month double-blind, partially randomized prospective study. Infants were fed a human milk–based diet (n = 23) or diets predominant in oleic acid (n = 19) or linoleic acid (n = 20) In the oleic acid group, LDL-C levels were increased significantly after 12 mo compared with after 4 mo Jones et al (2015)114 Human Subset of 50 participants from a randomized controlled trial in which 3 oil diets were consumed: a corn/safflower oil blend (25:75); high-oleic canola oil; and DHA-enriched high-oleic canola oil Consumption of high-oleic canola oil increased the percentage of cholesteryl oleate in LDL-C Aristizabal et al (2016)117 Human 54 abdominally obese individuals were matched by age and sex with individuals without abdominal obesity and were classified with metabolic syndrome according to the harmonizing criteria for metabolic syndrome Abdominally obese group with metabolic syndrome had higher levels of palmitic acid and oleic acid and lower levels of linoleic acid and arachidonic acid Wiberg et al (2006)118 Human Community-based prospective study of 2313 middle-aged men invited to a health survey at age 50 y. Duration of follow-up ranged up to 32 y Increased proportions of palmitic acid, palmitoleic acid, and oleic acid in cholesterol esters were associated with increased risk of stroke/transient ischemic attack Oda et al (2005)119 Human 31 men and 11 women without existing or a history of atherosclerotic cardiovascular disease or diabetes mellitus enrolled in the control group of a previous case-control study on n-3 PUFA intake as a negative risk factor for myocardial infarction Oleic acid, linoleic acid, and eicosapentaenoic acid were positively related to coronary risk factors Gilmore et al (2011)120 Human Crossover dietary intervention. 27 normocholesterolemic men consumed five 114-g ground beef patties weekly for 5 wk. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA) or 1.10 (high MUFA). High-MUFA ground beef provided 3.21 g more 18:1 (n-9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1 trans fatty acids per patty than did the low-MUFA ground beef Both ground beef interventions decreased HDL2 and HDL3 particle diameters relative to baseline values References . Species . Model/intervention . Potential adverse effects . Jeffery et al (1996)55 Rat Weanling male Lewis rats (n ≥ 6 for each diet) were fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic-acid sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control The olive oil and the high-oleic-acid sunflower oil diets both resulted in increased serum TAG compared with the low-fat and the safflower oil diets. Levels of serum TC increased in animals fed the high-fat diets and were highest in animals fed the olive oil or the high-oleic-acid sunflower oil diet Giudetti et al (2003)115 Rat Male Wistar rats were fed cholesterol-free diets containing stearic acid, oleic acid, or elaidic acid (n = 12/group) for 14 d Oleic acid increased the concentration of TAG in the liver compared with stearic acid Smith et al (1996)111 Swine Weanling pigs were fed diets containing added cornstarch (10 g/100 g chow) (to provide baseline data) or added fatty acids (10 g/100 g chow) for 35 d. Diets with added fatty acids contained ≈ 30% myristic acid plus the following: 36% myristoleic acid + palmitoleic acid combined; 52% palmitic acid; 51% stearic acid; 47% oleic acid; or 38% linoleic acid All diets caused a significant increase in TAG, TC, LDL-C, HDL-C, and VLDL-C. The increase in plasma TC from pretreatment values was greatest in pigs fed the myristoleic acid + palmitoleic acid and oleic acid diets. Increases in VLDL-C above pretreatment concentrations were lowest in palmitic acid–fed pigs and greatest in oleic acid–fed pigs Spreafico et al (2018)116 Nonhuman primate 20 common marmosets were fed 2 diets supplemented with either African palm oil or hybrid palm oil for 3 months. Hybrid palm oil had a higher level of oleic acid and a lower level of palmitic acid content than African palm oil Animals fed hybrid palm oil showed increased hepatic total lipid content and circulating transaminases, as well as an increased degree of fibrosis, without any apparent changes in plasma lipid levels or lipoprotein profile Mize et al (1995)112 Human 62 normal newborn infants. 12-month double-blind, partially randomized prospective study. Infants were fed a human milk–based diet (n = 23) or diets predominant in oleic acid (n = 19) or linoleic acid (n = 20) In the oleic acid group, LDL-C levels were increased significantly after 12 mo compared with after 4 mo Jones et al (2015)114 Human Subset of 50 participants from a randomized controlled trial in which 3 oil diets were consumed: a corn/safflower oil blend (25:75); high-oleic canola oil; and DHA-enriched high-oleic canola oil Consumption of high-oleic canola oil increased the percentage of cholesteryl oleate in LDL-C Aristizabal et al (2016)117 Human 54 abdominally obese individuals were matched by age and sex with individuals without abdominal obesity and were classified with metabolic syndrome according to the harmonizing criteria for metabolic syndrome Abdominally obese group with metabolic syndrome had higher levels of palmitic acid and oleic acid and lower levels of linoleic acid and arachidonic acid Wiberg et al (2006)118 Human Community-based prospective study of 2313 middle-aged men invited to a health survey at age 50 y. Duration of follow-up ranged up to 32 y Increased proportions of palmitic acid, palmitoleic acid, and oleic acid in cholesterol esters were associated with increased risk of stroke/transient ischemic attack Oda et al (2005)119 Human 31 men and 11 women without existing or a history of atherosclerotic cardiovascular disease or diabetes mellitus enrolled in the control group of a previous case-control study on n-3 PUFA intake as a negative risk factor for myocardial infarction Oleic acid, linoleic acid, and eicosapentaenoic acid were positively related to coronary risk factors Gilmore et al (2011)120 Human Crossover dietary intervention. 27 normocholesterolemic men consumed five 114-g ground beef patties weekly for 5 wk. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA) or 1.10 (high MUFA). High-MUFA ground beef provided 3.21 g more 18:1 (n-9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1 trans fatty acids per patty than did the low-MUFA ground beef Both ground beef interventions decreased HDL2 and HDL3 particle diameters relative to baseline values Abbreviations: DHA, docosahexaenoic acid; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; TAG, triglyceride; TC, total cholesterol; VLDL-C, very low-density lipoprotein cholesterol. Open in new tab Table 3 Potential adverse effects of oleic acid on lipid metabolism in animal and human studies References . Species . Model/intervention . Potential adverse effects . Jeffery et al (1996)55 Rat Weanling male Lewis rats (n ≥ 6 for each diet) were fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic-acid sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control The olive oil and the high-oleic-acid sunflower oil diets both resulted in increased serum TAG compared with the low-fat and the safflower oil diets. Levels of serum TC increased in animals fed the high-fat diets and were highest in animals fed the olive oil or the high-oleic-acid sunflower oil diet Giudetti et al (2003)115 Rat Male Wistar rats were fed cholesterol-free diets containing stearic acid, oleic acid, or elaidic acid (n = 12/group) for 14 d Oleic acid increased the concentration of TAG in the liver compared with stearic acid Smith et al (1996)111 Swine Weanling pigs were fed diets containing added cornstarch (10 g/100 g chow) (to provide baseline data) or added fatty acids (10 g/100 g chow) for 35 d. Diets with added fatty acids contained ≈ 30% myristic acid plus the following: 36% myristoleic acid + palmitoleic acid combined; 52% palmitic acid; 51% stearic acid; 47% oleic acid; or 38% linoleic acid All diets caused a significant increase in TAG, TC, LDL-C, HDL-C, and VLDL-C. The increase in plasma TC from pretreatment values was greatest in pigs fed the myristoleic acid + palmitoleic acid and oleic acid diets. Increases in VLDL-C above pretreatment concentrations were lowest in palmitic acid–fed pigs and greatest in oleic acid–fed pigs Spreafico et al (2018)116 Nonhuman primate 20 common marmosets were fed 2 diets supplemented with either African palm oil or hybrid palm oil for 3 months. Hybrid palm oil had a higher level of oleic acid and a lower level of palmitic acid content than African palm oil Animals fed hybrid palm oil showed increased hepatic total lipid content and circulating transaminases, as well as an increased degree of fibrosis, without any apparent changes in plasma lipid levels or lipoprotein profile Mize et al (1995)112 Human 62 normal newborn infants. 12-month double-blind, partially randomized prospective study. Infants were fed a human milk–based diet (n = 23) or diets predominant in oleic acid (n = 19) or linoleic acid (n = 20) In the oleic acid group, LDL-C levels were increased significantly after 12 mo compared with after 4 mo Jones et al (2015)114 Human Subset of 50 participants from a randomized controlled trial in which 3 oil diets were consumed: a corn/safflower oil blend (25:75); high-oleic canola oil; and DHA-enriched high-oleic canola oil Consumption of high-oleic canola oil increased the percentage of cholesteryl oleate in LDL-C Aristizabal et al (2016)117 Human 54 abdominally obese individuals were matched by age and sex with individuals without abdominal obesity and were classified with metabolic syndrome according to the harmonizing criteria for metabolic syndrome Abdominally obese group with metabolic syndrome had higher levels of palmitic acid and oleic acid and lower levels of linoleic acid and arachidonic acid Wiberg et al (2006)118 Human Community-based prospective study of 2313 middle-aged men invited to a health survey at age 50 y. Duration of follow-up ranged up to 32 y Increased proportions of palmitic acid, palmitoleic acid, and oleic acid in cholesterol esters were associated with increased risk of stroke/transient ischemic attack Oda et al (2005)119 Human 31 men and 11 women without existing or a history of atherosclerotic cardiovascular disease or diabetes mellitus enrolled in the control group of a previous case-control study on n-3 PUFA intake as a negative risk factor for myocardial infarction Oleic acid, linoleic acid, and eicosapentaenoic acid were positively related to coronary risk factors Gilmore et al (2011)120 Human Crossover dietary intervention. 27 normocholesterolemic men consumed five 114-g ground beef patties weekly for 5 wk. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA) or 1.10 (high MUFA). High-MUFA ground beef provided 3.21 g more 18:1 (n-9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1 trans fatty acids per patty than did the low-MUFA ground beef Both ground beef interventions decreased HDL2 and HDL3 particle diameters relative to baseline values References . Species . Model/intervention . Potential adverse effects . Jeffery et al (1996)55 Rat Weanling male Lewis rats (n ≥ 6 for each diet) were fed for 6 wk with diets containing 20% (by weight) olive oil, safflower oil, or high-oleic-acid sunflower oil; a low-fat diet containing 2.5% (by weight) lipid was used as control The olive oil and the high-oleic-acid sunflower oil diets both resulted in increased serum TAG compared with the low-fat and the safflower oil diets. Levels of serum TC increased in animals fed the high-fat diets and were highest in animals fed the olive oil or the high-oleic-acid sunflower oil diet Giudetti et al (2003)115 Rat Male Wistar rats were fed cholesterol-free diets containing stearic acid, oleic acid, or elaidic acid (n = 12/group) for 14 d Oleic acid increased the concentration of TAG in the liver compared with stearic acid Smith et al (1996)111 Swine Weanling pigs were fed diets containing added cornstarch (10 g/100 g chow) (to provide baseline data) or added fatty acids (10 g/100 g chow) for 35 d. Diets with added fatty acids contained ≈ 30% myristic acid plus the following: 36% myristoleic acid + palmitoleic acid combined; 52% palmitic acid; 51% stearic acid; 47% oleic acid; or 38% linoleic acid All diets caused a significant increase in TAG, TC, LDL-C, HDL-C, and VLDL-C. The increase in plasma TC from pretreatment values was greatest in pigs fed the myristoleic acid + palmitoleic acid and oleic acid diets. Increases in VLDL-C above pretreatment concentrations were lowest in palmitic acid–fed pigs and greatest in oleic acid–fed pigs Spreafico et al (2018)116 Nonhuman primate 20 common marmosets were fed 2 diets supplemented with either African palm oil or hybrid palm oil for 3 months. Hybrid palm oil had a higher level of oleic acid and a lower level of palmitic acid content than African palm oil Animals fed hybrid palm oil showed increased hepatic total lipid content and circulating transaminases, as well as an increased degree of fibrosis, without any apparent changes in plasma lipid levels or lipoprotein profile Mize et al (1995)112 Human 62 normal newborn infants. 12-month double-blind, partially randomized prospective study. Infants were fed a human milk–based diet (n = 23) or diets predominant in oleic acid (n = 19) or linoleic acid (n = 20) In the oleic acid group, LDL-C levels were increased significantly after 12 mo compared with after 4 mo Jones et al (2015)114 Human Subset of 50 participants from a randomized controlled trial in which 3 oil diets were consumed: a corn/safflower oil blend (25:75); high-oleic canola oil; and DHA-enriched high-oleic canola oil Consumption of high-oleic canola oil increased the percentage of cholesteryl oleate in LDL-C Aristizabal et al (2016)117 Human 54 abdominally obese individuals were matched by age and sex with individuals without abdominal obesity and were classified with metabolic syndrome according to the harmonizing criteria for metabolic syndrome Abdominally obese group with metabolic syndrome had higher levels of palmitic acid and oleic acid and lower levels of linoleic acid and arachidonic acid Wiberg et al (2006)118 Human Community-based prospective study of 2313 middle-aged men invited to a health survey at age 50 y. Duration of follow-up ranged up to 32 y Increased proportions of palmitic acid, palmitoleic acid, and oleic acid in cholesterol esters were associated with increased risk of stroke/transient ischemic attack Oda et al (2005)119 Human 31 men and 11 women without existing or a history of atherosclerotic cardiovascular disease or diabetes mellitus enrolled in the control group of a previous case-control study on n-3 PUFA intake as a negative risk factor for myocardial infarction Oleic acid, linoleic acid, and eicosapentaenoic acid were positively related to coronary risk factors Gilmore et al (2011)120 Human Crossover dietary intervention. 27 normocholesterolemic men consumed five 114-g ground beef patties weekly for 5 wk. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA) or 1.10 (high MUFA). High-MUFA ground beef provided 3.21 g more 18:1 (n-9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1 trans fatty acids per patty than did the low-MUFA ground beef Both ground beef interventions decreased HDL2 and HDL3 particle diameters relative to baseline values Abbreviations: DHA, docosahexaenoic acid; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; TAG, triglyceride; TC, total cholesterol; VLDL-C, very low-density lipoprotein cholesterol. Open in new tab In obese patients, fatty acids transported by plasma TAG lipoproteins may lead to their buildup in the organism, resulting in the activation of pathological processes.121 Both the levels and the profiles of serum TAGs can be disrupted by diets that provide preformed fatty acids and substrates for de novo hepatic synthesis of fatty acids.122 Guidetti et al115 investigated the hepatic fate of high concentrations of dietary oleic acid vs elaidic acid. A diet rich in stearic acid was given to control rats to evaluate the specific effects of oleic and elaidic acids. Compared with stearic acid, both oleic acid and C18:1 trans isomers increased the hepatic concentration of TAGs.115 More recently, in a 3-month dietary intervention, 20 primates were given 2 hyperlipidic diets that differed only in their source of lipid: African palm oil or hybrid palm oil, the latter having a higher content of oleic acid and a lower content of palmitic acid than the former.116 Animals fed hybrid palm oil showed increases in hepatic total lipid content and circulating transaminases, together with increased fibrosis, even though plasma lipid levels and the lipoprotein profile were barely affected. Nevertheless, the deleterious effects of excessive palmitic acid intake are widely described. Unfavorable habits such as chronic consumption of high-carbohydrate diets and a sedentary lifestyle might disrupt the balance between PUFAs and palmitic acid, which can give rise to high accumulation of palmitic acid in tissues, leading to hyperlipidemia, increased ectopic fat build-up, hyperglycemia, insulin resistance, and increased inflammation.123–125 Intake of palmitic acid (and other fatty acids that can be synthesized from it, such as palmitoleic and oleic acids) has been positively correlated with several features of metabolic syndrome.117,126,127 In a cross-sectional study, Maximino et al128 investigated the association between fatty acid intake and metabolic syndrome status among overweight and obese women. Overweight women with metabolic syndrome consumed higher amounts of MUFAs, PUFAs, and linoleic acid than overweight women without metabolic syndrome. Higher consumption of linoleic acid was also observed in obese women with metabolic syndrome compared with obese women without metabolic syndrome.128 A higher incidence of metabolic syndrome was significantly associated with increased intake of monounsaturated, polyunsaturated, linoleic, and trans fatty acids. The authors of that study suggest that lipid consumption might be related to metabolic syndrome, yet acknowledge the possible influence of other factors such as lifestyle, genetics, and metabolism. The associations between unsaturated fatty acids and coronary risk factors are arguable. Most studies have associated consumption of linoleic acid with improved cardiovascular prognosis. For example, in a sample of middle-aged men, a 32-year follow-up showed that increased amounts of palmitic, palmitoleic, and oleic acids were related to a higher risk for stroke/transient ischemic attack, whereas a higher proportion of linoleic acid was protective.118 Nevertheless, even though the outcomes of randomized controlled trials indicate that exchanging dietary saturated fat with linoleic acid successfully lowers circulating cholesterol, the hypothesis that linoleic acid results in a lower risk of death from coronary heart disease or all-cause deaths is unproven.129 It has been suggested that publication bias led, in part, to an overemphasis of the positive effects of substituting saturated fat with linoleic acid–rich vegetable oils.129 Moreover, Oda et al119 found a positive association between coronary risk factors and oleic acid, linoleic acid, and eicosapentaenoic acid. Hydroxytyrosol in olive oil As mentioned above, phenolic compounds in olive oil play a key role in the health benefits attributed to EVOO and VOO.91,130–132 To examine the role of hydroxytyrosol, the most abundant phenolic compound in olive oil, bibliographic searches were conducted to identify potential adverse effects of in vivo supplementation with hydroxytyrosol on lipid metabolism. PubMed and Scopus databases were searched to explore any potential negative impacts of hydroxytyrosol consumption on lipid metabolism. The keyword “hydroxytyrosol” was combined with “lipid metabolism,” “triglycerides,” “cholesterol,” “lipid synthesis,” “lipid profile,” or “lipoprotein.” Articles were critically reviewed, and those reporting adverse effects on lipid metabolism in vivo, both in healthy and in disease-induced models, were summarized (Table 4).133–137 Table 4 Potential adverse effects of hydroxytyrosol on lipid metabolism in animal studies Reference . Species . Model/intervention . Potential adverse effects . Tomé-Carneiro et al (2016)133 Mouse Healthy C57BL/6J mice. Fed control diet or control diet plus hydroxytyrosol (0.03 g%) for 8 wk Hydroxytyrosol administration increased TAG levels but had no effect on TC Acín et al (2006)134 Mouse ApoE-deficient male mice. Treated with hydroxytyrosol (10 mg/kg/d) for 10 wk Hydroxytyrosol group showed decreased apolipoprotein A-I and increased TC. No significant changes in HDL-C, paraoxonase, apolipoprotein B, or TAGs Rodríguez-Gutiérrez et al (2012)135 Rat Vitamin E–deficient Rowett Hooded Lister male rats. Received vitamin E–adequate diet (100 mg dα-tocopherol/kg diet) (CtE+); vitamin E–deficient diet containing vitamin E at < 0.5 mg/kg diet (CtE−); CtE− + alperujo extract (100 mg/kg diet) (CtE-AE); CtE− + hydroxytyrosol (100 mg/kg diet) (CtE-HT); CtE− + dα-tocopherol (vitamin E) (100 mg/kg diet) (CtE-DT); or CtE− + DHPG (10 mg/kg diet) (CtE-DHPG).CtE+ and CtE− groups treated for 12 wk.CtE-AE, CtE-HT, CtE-DT, and CtE-DHPG groups treated for 10 wk with CtE−, followed by 2-wk treatment with alperujo extract, hydroxytyrosol, dα-tocopherol, or DHPG Hydroxytyrosol group showed increased plasma TAGs compared with the vitamin E–deficient group. No effect on final body weight, TC, or hepatic TAGs or fat Faine et al (2006)136 Rat Male Wistar rats. Received control diet or treatment with extra-virgin olive oil (7.5 mL/kg twice weekly); oleic acid (3.45 mL/kg twice weekly); or hydroxytyrosol (7.5 mg/kg twice weekly) for 30 d No effect on body weight, TC, LDL-C, HDL-C, or TAGs. Hydroxytyrosol induced elevated TAG and lipid hydroperoxide concentrations in cardiac muscle Vazquez-Gomez et al (2017)137 Swine Iberian sows with diet-increased risk of IUGR. Fed control diet or control diet plus hydroxytyrosol (1.5 mg/kg/d). Administered from day 35 to delivery Hydroxytyrosol-treated sows vs control sows showed higher mean birth weight and body weight at weaning, increased TAG plasma concentrations, and decreased TC and LDL-C plasma concentrations but no change in HDL-C plasma concentrations Reference . Species . Model/intervention . Potential adverse effects . Tomé-Carneiro et al (2016)133 Mouse Healthy C57BL/6J mice. Fed control diet or control diet plus hydroxytyrosol (0.03 g%) for 8 wk Hydroxytyrosol administration increased TAG levels but had no effect on TC Acín et al (2006)134 Mouse ApoE-deficient male mice. Treated with hydroxytyrosol (10 mg/kg/d) for 10 wk Hydroxytyrosol group showed decreased apolipoprotein A-I and increased TC. No significant changes in HDL-C, paraoxonase, apolipoprotein B, or TAGs Rodríguez-Gutiérrez et al (2012)135 Rat Vitamin E–deficient Rowett Hooded Lister male rats. Received vitamin E–adequate diet (100 mg dα-tocopherol/kg diet) (CtE+); vitamin E–deficient diet containing vitamin E at < 0.5 mg/kg diet (CtE−); CtE− + alperujo extract (100 mg/kg diet) (CtE-AE); CtE− + hydroxytyrosol (100 mg/kg diet) (CtE-HT); CtE− + dα-tocopherol (vitamin E) (100 mg/kg diet) (CtE-DT); or CtE− + DHPG (10 mg/kg diet) (CtE-DHPG).CtE+ and CtE− groups treated for 12 wk.CtE-AE, CtE-HT, CtE-DT, and CtE-DHPG groups treated for 10 wk with CtE−, followed by 2-wk treatment with alperujo extract, hydroxytyrosol, dα-tocopherol, or DHPG Hydroxytyrosol group showed increased plasma TAGs compared with the vitamin E–deficient group. No effect on final body weight, TC, or hepatic TAGs or fat Faine et al (2006)136 Rat Male Wistar rats. Received control diet or treatment with extra-virgin olive oil (7.5 mL/kg twice weekly); oleic acid (3.45 mL/kg twice weekly); or hydroxytyrosol (7.5 mg/kg twice weekly) for 30 d No effect on body weight, TC, LDL-C, HDL-C, or TAGs. Hydroxytyrosol induced elevated TAG and lipid hydroperoxide concentrations in cardiac muscle Vazquez-Gomez et al (2017)137 Swine Iberian sows with diet-increased risk of IUGR. Fed control diet or control diet plus hydroxytyrosol (1.5 mg/kg/d). Administered from day 35 to delivery Hydroxytyrosol-treated sows vs control sows showed higher mean birth weight and body weight at weaning, increased TAG plasma concentrations, and decreased TC and LDL-C plasma concentrations but no change in HDL-C plasma concentrations Abbreviations: ApoE, apolipoprotein E; DPHG, 3,4-dihydroxyphenylglycol; HDL-C, high-density lipoprotein cholesterol; IUGR, intrauterine growth restriction; LDL-C, low-density lipoprotein cholesterol; TAG, triglyceride; TC, total cholesterol. Open in new tab Table 4 Potential adverse effects of hydroxytyrosol on lipid metabolism in animal studies Reference . Species . Model/intervention . Potential adverse effects . Tomé-Carneiro et al (2016)133 Mouse Healthy C57BL/6J mice. Fed control diet or control diet plus hydroxytyrosol (0.03 g%) for 8 wk Hydroxytyrosol administration increased TAG levels but had no effect on TC Acín et al (2006)134 Mouse ApoE-deficient male mice. Treated with hydroxytyrosol (10 mg/kg/d) for 10 wk Hydroxytyrosol group showed decreased apolipoprotein A-I and increased TC. No significant changes in HDL-C, paraoxonase, apolipoprotein B, or TAGs Rodríguez-Gutiérrez et al (2012)135 Rat Vitamin E–deficient Rowett Hooded Lister male rats. Received vitamin E–adequate diet (100 mg dα-tocopherol/kg diet) (CtE+); vitamin E–deficient diet containing vitamin E at < 0.5 mg/kg diet (CtE−); CtE− + alperujo extract (100 mg/kg diet) (CtE-AE); CtE− + hydroxytyrosol (100 mg/kg diet) (CtE-HT); CtE− + dα-tocopherol (vitamin E) (100 mg/kg diet) (CtE-DT); or CtE− + DHPG (10 mg/kg diet) (CtE-DHPG).CtE+ and CtE− groups treated for 12 wk.CtE-AE, CtE-HT, CtE-DT, and CtE-DHPG groups treated for 10 wk with CtE−, followed by 2-wk treatment with alperujo extract, hydroxytyrosol, dα-tocopherol, or DHPG Hydroxytyrosol group showed increased plasma TAGs compared with the vitamin E–deficient group. No effect on final body weight, TC, or hepatic TAGs or fat Faine et al (2006)136 Rat Male Wistar rats. Received control diet or treatment with extra-virgin olive oil (7.5 mL/kg twice weekly); oleic acid (3.45 mL/kg twice weekly); or hydroxytyrosol (7.5 mg/kg twice weekly) for 30 d No effect on body weight, TC, LDL-C, HDL-C, or TAGs. Hydroxytyrosol induced elevated TAG and lipid hydroperoxide concentrations in cardiac muscle Vazquez-Gomez et al (2017)137 Swine Iberian sows with diet-increased risk of IUGR. Fed control diet or control diet plus hydroxytyrosol (1.5 mg/kg/d). Administered from day 35 to delivery Hydroxytyrosol-treated sows vs control sows showed higher mean birth weight and body weight at weaning, increased TAG plasma concentrations, and decreased TC and LDL-C plasma concentrations but no change in HDL-C plasma concentrations Reference . Species . Model/intervention . Potential adverse effects . Tomé-Carneiro et al (2016)133 Mouse Healthy C57BL/6J mice. Fed control diet or control diet plus hydroxytyrosol (0.03 g%) for 8 wk Hydroxytyrosol administration increased TAG levels but had no effect on TC Acín et al (2006)134 Mouse ApoE-deficient male mice. Treated with hydroxytyrosol (10 mg/kg/d) for 10 wk Hydroxytyrosol group showed decreased apolipoprotein A-I and increased TC. No significant changes in HDL-C, paraoxonase, apolipoprotein B, or TAGs Rodríguez-Gutiérrez et al (2012)135 Rat Vitamin E–deficient Rowett Hooded Lister male rats. Received vitamin E–adequate diet (100 mg dα-tocopherol/kg diet) (CtE+); vitamin E–deficient diet containing vitamin E at < 0.5 mg/kg diet (CtE−); CtE− + alperujo extract (100 mg/kg diet) (CtE-AE); CtE− + hydroxytyrosol (100 mg/kg diet) (CtE-HT); CtE− + dα-tocopherol (vitamin E) (100 mg/kg diet) (CtE-DT); or CtE− + DHPG (10 mg/kg diet) (CtE-DHPG).CtE+ and CtE− groups treated for 12 wk.CtE-AE, CtE-HT, CtE-DT, and CtE-DHPG groups treated for 10 wk with CtE−, followed by 2-wk treatment with alperujo extract, hydroxytyrosol, dα-tocopherol, or DHPG Hydroxytyrosol group showed increased plasma TAGs compared with the vitamin E–deficient group. No effect on final body weight, TC, or hepatic TAGs or fat Faine et al (2006)136 Rat Male Wistar rats. Received control diet or treatment with extra-virgin olive oil (7.5 mL/kg twice weekly); oleic acid (3.45 mL/kg twice weekly); or hydroxytyrosol (7.5 mg/kg twice weekly) for 30 d No effect on body weight, TC, LDL-C, HDL-C, or TAGs. Hydroxytyrosol induced elevated TAG and lipid hydroperoxide concentrations in cardiac muscle Vazquez-Gomez et al (2017)137 Swine Iberian sows with diet-increased risk of IUGR. Fed control diet or control diet plus hydroxytyrosol (1.5 mg/kg/d). Administered from day 35 to delivery Hydroxytyrosol-treated sows vs control sows showed higher mean birth weight and body weight at weaning, increased TAG plasma concentrations, and decreased TC and LDL-C plasma concentrations but no change in HDL-C plasma concentrations Abbreviations: ApoE, apolipoprotein E; DPHG, 3,4-dihydroxyphenylglycol; HDL-C, high-density lipoprotein cholesterol; IUGR, intrauterine growth restriction; LDL-C, low-density lipoprotein cholesterol; TAG, triglyceride; TC, total cholesterol. Open in new tab In terms of safety, most studies have not detected adverse effects of hydroxytyrosol consumption, and 2 ad hoc studies have confirmed the safety profile of hydroxytyrosol.138,139 The aforementioned EFSA health claim regarding phenolic compounds in olive oil (see section Recommendations for Olive Oil Consumption) refers to hydroxytyrosol and its derivatives and focuses on the protection provided to LDL-C particles against oxidative damage.34 Of note, this health claim does not address any effect of hydroxytyrosol on maintenance of normal lipid metabolism, blood pressure, or other biological actions. Most studies in humans and other animal models, including mice, rats, rabbits, and zebrafish, have generally shown either a beneficial effect or no effect of hydroxytyrosol consumption on circulating lipid markers and lipid peroxidation.140–145 Nevertheless, both dyslipidemia and hepatic fat accumulation were reported in rodents after EVOO consumption.41 In one example, an 8-week supplementation with a dietarily attainable amount of hydroxytyrosol resulted in hypertriglyceridemia in mice.133 Moreover, after a 10-week vitamin E–deficient diet, a 2-week supplementation with hydroxytyrosol at 100 mg/kg of diet led to a rise in plasma TAGs in Rowett Hooded Lister rats.135 In Wistar rats, hydroxytyrosol supplementation (7.5 mg/kg diet, twice a week, for 30 days) induced elevated concentrations of TAG and lipid hydroperoxide in cardiac muscle.136 In a nonmurine model, supplementation with hydroxytyrosol (1.5 mg/kg/d) from day 35 to delivery resulted in raised TAGs in the offspring of Iberian sows with diet-induced risk of intrauterine growth restriction compared with controls.137 In humans, 2 studies reported no changes in lipid profiles after hydroxytyrosol consumption.146,147 In a study with healthy volunteers, intake of 0 mg, 5 mg, or 25 mg of hydroxytyrosol per day for 1 week did not produce any significant effects on levels of TC, LDL-C, HDL-C, or TAGs or on body weight.148 Another study in healthy individuals found that a 3-week supplementation with hydroxytyrosol (15 mg/d) vs placebo did not cause any significant change in TC, HDL-C, or TAGs, whereas malondialdehyde levels were significantly reduced.149 Finally, when 2 groups of male apolipoprotein E–deficient mice received a standard chow diet plus water (controls) or an aqueous solution of hydroxytyrosol (10 mg/kg/d) for 10 weeks, the group that received hydroxytyrosol showed significant reductions in apolipoprotein A-I and increases in TC, with no changes in HDL-C, paraoxonase, apolipoprotein B, or TAGs.134 PUTATIVE MECHANISMS OF ACTION OF EXCESSIVE OLIVE OIL INTAKE Thermodynamics dictate that a calorie is a calorie, regardless of its source. Fat is the most caloric macronutrient, whether it is composed of saturated fatty acids, MUFAs, or PUFAs. Disproportionate caloric intake and concomitant low energy expenditure leads to weight gain, high body mass index, and obesity, which is associated with a variety of chronic diseases.4 With regard to olive oil, there is popular belief that, because of its high proportion of oleic acid, overconsumption is quite harmless. While the replacement of saturated fatty acids with MUFAs likely affords cardiovascular protection, the effects of oleic acid on human health are equivocal, at best.14 Indeed, there is some, albeit scant, evidence that associates circulating oleic acid concentrations with worse cardiovascular prognosis. For example, in a metabolomic profiling study, MUFA levels were associated with increased cardiovascular risk, while higher levels of n-6 fatty acids and docosahexaenoic acid were associated with lower risk.150 For example, Block et al151 reported that the content of oleic acid in the blood cell membranes of patients with acute coronary syndrome was significantly higher than that of controls. Finally, the effects of oleic acid on plasma cholesterol concentrations are very modest and unlikely to provide significant cardioprotective benefits.12 From a molecular biology perspective, fatty acid overload and heightened substrate competition result in mitochondrial indecision, impaired fuel switching, and energy dysregulation, known as metabolic inflexibility.152 In summary, the inordinate use of fat—even fat from olive oil—should be avoided, and the advice to keep fat intake within 30% of total calories is still valid. Although (poly)phenols are minor components of EVOO, they are sensed by the body as xenobiotics and, thus, as mildly toxic compounds. Indeed, humans do not store (poly)phenols, which activate phase II enzymes148 (at least in in vitro models) via the Nrf2 (nuclear factor erythroid 2–related factor 2) pathway. (Poly)phenol toxicity from dietary exposure is very unlikely, but there are reports of hepatic damage by, for example, green tea catechins following excessive use of supplements, when the ingested amounts overload the metabolic machinery.77 In brief, extreme emphasis on the healthful properties of (poly)phenols, including those in olive oil, might result in inordinate commercialization of nutraceuticals, the safety of which is poorly assessed. CONCLUSION The reported detrimental effects of excessive olive oil consumption on lipid metabolism are mostly outweighed by the numerous health benefits of olive oil. Indeed, the use of olive oil as the principal source of fat is generally recognized as beneficial and safe by the EFSA and the FDA. Nevertheless, too much of a good thing is to be avoided, as excessive intake might impair lipid metabolism. Of the major fatty acids in olive oil, oleic acid likely has minimal physiological actions. Some studies, however, have reported adverse effects of oleic acid when administered in large amounts and as an isolated component, which is vastly different from real-life circumstances. Most studies of linoleic acid focus on its cholesterol-lowering properties, whereas those of palmitic acid have shown that high consumption increases cholesterolemia. Even though the phenolic compound hydroxytyrosol has been proven safe, some studies have shown it to have adverse effects on lipid metabolism, possibly explained by metabolic differences between rodents and humans (including differences in metabolites produced during metabolism of (poly)phenols). Moreover, the well-known bias toward the preferential publication of positive results could partially explain the low number of studies in which adverse effects of excessive olive oil consumption have been reported. In any case, postprandial lipemia (especially in individuals with dyslipidemia or diabetes) is a cardiovascular risk factor and has been reported following olive oil consumption. Thus, while EVOO is healthful and should be used preferentially within the context of a balanced diet, excessive consumption should be avoided. Acknowledgments Author contributions. A.D. and F.V. designed the research. J.T-C., M.C.C., and M.C.L.H. conducted the research and wrote the manuscript. A.D. and F.V. examined the initial draft critically and revised it. All authors reviewed and approved the manuscript. Declaration of interest. The authors have no relevant interests to declare. Funding/support. This research was funded by grants (CIVP18A3888) from the Fundación Ramón Areces, Madrid, Spain, to A.D., J.T-C., F.V., and M.C.C.; by the Agencia Estatal de Investigación, Madrid, Spain; by European FEDER Funds (AGL2016-78922-R) to A.D.; and by a grant from the Regione del Veneto (POR FESR 3S4H), Venice, Italy, to F.V. M.C.L.H. was supported by a contract from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid, Fondo Social Europeo, and Iniciativa de Empleo Juvenil YEI (PEJD-2016/BIO-2781). None of the funders had any role in the conception, design, performance, or approval of this work. References 1 Wang SY , Tan ASL, Claggett B, et al. . Longitudinal associations between income changes and incident cardiovascular disease . JAMA Cardiol. 2019 ; 4 : 1203 – 1212 . Google Scholar Crossref Search ADS PubMed WorldCat 2 World Health Organization. Diet, Nutrition, and the Prevention of Chronic Diseases: Report of a Joint WHO/FAO Expert Consultation . 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TI - Olive oil consumption and its repercussions on lipid metabolism
JF - Nutrition Reviews
DO - 10.1093/nutrit/nuaa014
DA - 2020-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/olive-oil-consumption-and-its-repercussions-on-lipid-metabolism-WqcBy0za1P
SP - 952
EP - 968
VL - 78
IS - 11
DP - DeepDyve
ER -