Measure for measure?

Measure for measure? The capacity to synthesize fatty acids (FAs) de novo from acetyl-CoA, and thereby from nonlipid precursors of acetyl-CoA, is almost universally present in cells. Functions of de novo lipogenesis (DNL) remain uncertain, particularly in human biology, but in recent years new functions have been discovered and new pathogenic roles have been identified in human disease—particularly in nonalcoholic fatty liver disease (NAFLD). It is clear that most of the FAs in human lipid stores derive from dietary fat, not from DNL (1–3). This is not the case in other animals (pigs or cows during fattening, honeybees making wax) and in some human tissues (developing brain relies almost entirely on DNL and de novo cholesterol synthesis for myelination). DNL likely also may play a signaling role in many important processes (e.g., muscle cell fuel selection, hypothalamic appetite control, and pancreatic β-cell signaling). But the area of highest interest for DNL these days is NAFLD, because of the remarkable rise of NAFLD to epidemic proportions over the past 30 y. And elevated DNL is now increasingly recognized as a fundamental characteristic of NAFLD (4–6). Both basic cell biology and clinical metabolism have brought important advances to our understanding of how DNL fits into the NAFLD story. The seminal finding (7) that the sterol regulatory element-binding protein (SRE-BP) cleavage-activating protein (SCAP)/SRE-BP pathway regulates not only cholesterol homeostasis but also DNL provides a link between the FA synthesis and cholesterol synthesis pathways, with implications for hepatic lipoprotein assembly and secretion. The combination of high rates of hepatic DNL (an insulin-stimulated pathway) and hepatic insulin resistance (to suppression of glucose production) (8) in NAFLD provides clinical evidence for the important concept of pathway-selective insulin resistance in cells. The DNL/insulin resistance interplay also provides an attractive pathogenic narrative for the evolution of NAFLD—compensatory hyperinsulinemia as a driver of hepatic DNL and fat accrual—and implicates DNL as both a potentially central diagnostic biomarker and a treatment target in NAFLD. The recent availability of effective pharmacologic inhibitors of key enzymes in the DNL pathway—such as acetyl-CoA carboxylase and ATP-citrate lyase—has brought the physiologic and pathophysiologic roles of DNL in humans to a position of practical importance (6, 9). Work with acetyl-CoA carboxylase inhibitors, for example, may uncover unexpected functions of DNL. For all these reasons, accurate measurement of hepatic DNL in humans is of increasing importance. The direct measurement of hepatic DNL synthesis rates is easy, in practice, using stable isotope administration, particularly oral intake of heavy water (4, 6), although it does require mass spectrometric facilities. Longer labeling studies are required for accurate DNL measurement in NAFLD because the enlarged hepatic triglyceride storage pool turns over slowly, with a half-life of 7–14 d (6). In healthy subjects, shorter labeling (3 d) with heavy water is adequate to achieve plateau DNL values. Overnight labeling, with heavy water or 13C-acetate, is useful for measuring fasting DNL or to test the acute pharmacodynamics of DNL inhibitors (9), but does not accurately reveal integrated DNL throughout the circadian cycle over days or weeks (6). There are disadvantages to the metabolic labeling approach, however. Stored or archived plasma samples cannot be interrogated post hoc, and new investigations require subjects or patients to receive a label in advance. It would be easier if a circulating FA measurement could replace metabolic labeling as a measure of DNL. Some studies have suggested that circulating FA ratios might be useful markers of DNL, as substitutes for metabolic labeling. In particular, the “lipogenic index” (ratio of 16:0 to 18:2n–6) and the stearyl-CoA desaturase index (SCD, 16:1n–7 to 16:0) have been proposed to accurately reflect hepatic DNL, but results have been mixed (10, 11). In the current issue of The American Journal of Clinical Nutrition, Rosqvist et al. (12) measured hepatic DNL by overnight heavy water labeling in 149 healthy human subjects and asked whether circulating FA markers were useful as substitute metrics. They report no significant correlations between measured DNL and the ratios 16:0 to 18:2n–6 or 16:1n–7 to 16:0 (lipogenic and SCD indexes, respectively) or the mole percentages of 16:1n–7, 18:1n–7, and 18:1n–9. Weak correlations were found for DNL compared with percentages of 14:0, 16:0, or 18:0 (r < 0.35). When they divided subjects into 2 groups—high or low, relative to a median value of 6.5%—only percentages of 14:0 or 18:0 showed even a weak discriminatory power. Other markers, such as FA ratios in plasma cholesterol-esters or phospholipids or in red cell phospholipids, also did not discriminate high- from low-DNL subjects. The expected physiologic correlations with hepatic DNL in their study group were upheld (higher fasting insulin and triglyceride concentrations, BMI, and waist circumference). The authors concluded that circulating FA concentrations or ratios have limited usefulness as surrogate markers for hepatic DNL and that diagnostic values are poor for discriminating high- from low-DNL subjects, in healthy people on their habitual diets. This study has some limitations. Subjects were healthy volunteers, not individuals with NAFLD. The hepatic DNL measurement was by overnight labeling for only 12 h, and assessed fasting DNL, not fed or cumulative DNL around the clock. Median DNL was 6.5%, but is much higher in NAFLD (4) and even higher in nonalcoholic steatohepatitis (>40%) (6). This was an outpatient study, so diet and ethanol intake were not controlled. But, as the authors point out, these are real-world settings and are how previous studies that compared blood FA markers were carried out. It looks like there are not yet any easy plasma lipid markers to replace direct measurement of hepatic DNL. But the question deserves continued inquiry. Future studies might focus on subjects with high values for hepatic DNL (individuals with NAFLD, insulin resistance, or type 2 diabetics) or on settings such as fructose or simple sugar intake, and might use longer periods of heavy water labeling. In the meantime, the role of DNL in human metabolism will likely surprise us. And outpatient use of heavy water remains a safe and relatively simple way to measure it. Acknowledgements The sole author was responsible for all aspects of the manuscript. The author reports no conflicts of interest. Notes Abbreviations used: DNL, de novo lipogenesis; FA, fatty acid; NAFLD, nonalcoholic fatty liver disease. References 1. Hirsch J . Fatty acid patterns in human adipose tissue . In: Cahill JF , Renold AE editors. Terjung , R editors. Handbook of Physiology: Adipose Tissue . Washington (DC) : American Physiological Society ; 1965 . p. 181 – 9 .. Reprinted in, editor. Comprehensive physiology; 2011 . 2. Hellerstein MK , Schwarz JM , Neese RA . Regulation of hepatic de novo lipogenesis in humans . Annu Rev Nutr . 1996 ; 16 : 523 – 57 . Google Scholar Crossref Search ADS PubMed 3. Strawford A , Antelo F , Christiansen M , Hellerstein MK . Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O . Am J Physiol Endocrinol Metab . 2004 ; 286 ( 4 ): E577 – 88 . Google Scholar Crossref Search ADS PubMed 4. Lambert JE , Ramos-Roman MA , Browning JD , Parks EJ . Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease . Gastroenterology . 2014 ; 146 ( 3 ): 726 – 35 . Google Scholar Crossref Search ADS PubMed 5. Donnelly KL , Smith CI , Schwarzenberg SJ , Jessurun J , Boldt MD , Parks EJ . Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease . J Clin Invest . 2005 ; 115 ( 5 ): 1343 – 51 . Google Scholar Crossref Search ADS PubMed 6. Lawitz EJ , Coste A , Poordad F , Alkhouri N , Loo N , McColgan BJ , Tarrant JM , Nguyen T , Han L , Chung C et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis . Clin Gastroenterol Hepatol . 2018 ; 16 ( 12 ): 1983 – 91.e3 . Google Scholar Crossref Search ADS PubMed 7. Moon YA , Liang G , Xie X , Frank-Kamenetsky M , Fitzgerald K , Koteliansky V , Brown MS , Goldstein JL , Horton JD . The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals . Cell Metab . 2012 ; 15 ( 2 ): 240 – 6 . Google Scholar Crossref Search ADS PubMed 8. Fabbrini E , Magkos F , Mohammed BS , Pietka T , Abumrad NA , Patterson BW , Okunade A , Klein S . Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity . Proc Natl Acad Sci U S A . 2009 ; 106 ( 36 ): 15430 – 5 . Google Scholar Crossref Search ADS PubMed 9. Stiede K , Miao W , Blanchette HS , Beysen C , Harriman G , Harwood HJ Jr , Kelley H , Kapeller R , Schmalbach T , Westlin WF . Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study . Hepatology . 2017 ; 66 ( 2 ): 324 – 34 . Google Scholar Crossref Search ADS PubMed 10. Lee JJ , Lambert JE , Hovhannisyan Y , Ramos-Roman MA , Trombold JR , Wagner DA , Parks EJ . Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis . Am J Clin Nutr . 2015 ; 101 ( 1 ): 34 – 43 . Google Scholar Crossref Search ADS PubMed 11. Hudgins LC , Hellerstein MK , Seidman CE , Neese RA , Tremaroli JD , Hirsch J . Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects . J Lipid Res . 2000 ; 41 ( 4 ): 595 – 604 . Google Scholar PubMed 12. Rosqvist F , McNeil CA , Pramfalk C , Parry SA , Low WS , Cornfield T , Fielding BA , Hodson L . Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers . Am J Clin Nutr . 2019 ; 109 ( 2 ): In Press . © 2019 American Society for Nutrition. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Clinical Nutrition Oxford University Press

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Publisher
Oxford University Press
Copyright
© 2019 American Society for Nutrition.
ISSN
0002-9165
eISSN
1938-3207
D.O.I.
10.1093/ajcn/nqy365
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Abstract

The capacity to synthesize fatty acids (FAs) de novo from acetyl-CoA, and thereby from nonlipid precursors of acetyl-CoA, is almost universally present in cells. Functions of de novo lipogenesis (DNL) remain uncertain, particularly in human biology, but in recent years new functions have been discovered and new pathogenic roles have been identified in human disease—particularly in nonalcoholic fatty liver disease (NAFLD). It is clear that most of the FAs in human lipid stores derive from dietary fat, not from DNL (1–3). This is not the case in other animals (pigs or cows during fattening, honeybees making wax) and in some human tissues (developing brain relies almost entirely on DNL and de novo cholesterol synthesis for myelination). DNL likely also may play a signaling role in many important processes (e.g., muscle cell fuel selection, hypothalamic appetite control, and pancreatic β-cell signaling). But the area of highest interest for DNL these days is NAFLD, because of the remarkable rise of NAFLD to epidemic proportions over the past 30 y. And elevated DNL is now increasingly recognized as a fundamental characteristic of NAFLD (4–6). Both basic cell biology and clinical metabolism have brought important advances to our understanding of how DNL fits into the NAFLD story. The seminal finding (7) that the sterol regulatory element-binding protein (SRE-BP) cleavage-activating protein (SCAP)/SRE-BP pathway regulates not only cholesterol homeostasis but also DNL provides a link between the FA synthesis and cholesterol synthesis pathways, with implications for hepatic lipoprotein assembly and secretion. The combination of high rates of hepatic DNL (an insulin-stimulated pathway) and hepatic insulin resistance (to suppression of glucose production) (8) in NAFLD provides clinical evidence for the important concept of pathway-selective insulin resistance in cells. The DNL/insulin resistance interplay also provides an attractive pathogenic narrative for the evolution of NAFLD—compensatory hyperinsulinemia as a driver of hepatic DNL and fat accrual—and implicates DNL as both a potentially central diagnostic biomarker and a treatment target in NAFLD. The recent availability of effective pharmacologic inhibitors of key enzymes in the DNL pathway—such as acetyl-CoA carboxylase and ATP-citrate lyase—has brought the physiologic and pathophysiologic roles of DNL in humans to a position of practical importance (6, 9). Work with acetyl-CoA carboxylase inhibitors, for example, may uncover unexpected functions of DNL. For all these reasons, accurate measurement of hepatic DNL in humans is of increasing importance. The direct measurement of hepatic DNL synthesis rates is easy, in practice, using stable isotope administration, particularly oral intake of heavy water (4, 6), although it does require mass spectrometric facilities. Longer labeling studies are required for accurate DNL measurement in NAFLD because the enlarged hepatic triglyceride storage pool turns over slowly, with a half-life of 7–14 d (6). In healthy subjects, shorter labeling (3 d) with heavy water is adequate to achieve plateau DNL values. Overnight labeling, with heavy water or 13C-acetate, is useful for measuring fasting DNL or to test the acute pharmacodynamics of DNL inhibitors (9), but does not accurately reveal integrated DNL throughout the circadian cycle over days or weeks (6). There are disadvantages to the metabolic labeling approach, however. Stored or archived plasma samples cannot be interrogated post hoc, and new investigations require subjects or patients to receive a label in advance. It would be easier if a circulating FA measurement could replace metabolic labeling as a measure of DNL. Some studies have suggested that circulating FA ratios might be useful markers of DNL, as substitutes for metabolic labeling. In particular, the “lipogenic index” (ratio of 16:0 to 18:2n–6) and the stearyl-CoA desaturase index (SCD, 16:1n–7 to 16:0) have been proposed to accurately reflect hepatic DNL, but results have been mixed (10, 11). In the current issue of The American Journal of Clinical Nutrition, Rosqvist et al. (12) measured hepatic DNL by overnight heavy water labeling in 149 healthy human subjects and asked whether circulating FA markers were useful as substitute metrics. They report no significant correlations between measured DNL and the ratios 16:0 to 18:2n–6 or 16:1n–7 to 16:0 (lipogenic and SCD indexes, respectively) or the mole percentages of 16:1n–7, 18:1n–7, and 18:1n–9. Weak correlations were found for DNL compared with percentages of 14:0, 16:0, or 18:0 (r < 0.35). When they divided subjects into 2 groups—high or low, relative to a median value of 6.5%—only percentages of 14:0 or 18:0 showed even a weak discriminatory power. Other markers, such as FA ratios in plasma cholesterol-esters or phospholipids or in red cell phospholipids, also did not discriminate high- from low-DNL subjects. The expected physiologic correlations with hepatic DNL in their study group were upheld (higher fasting insulin and triglyceride concentrations, BMI, and waist circumference). The authors concluded that circulating FA concentrations or ratios have limited usefulness as surrogate markers for hepatic DNL and that diagnostic values are poor for discriminating high- from low-DNL subjects, in healthy people on their habitual diets. This study has some limitations. Subjects were healthy volunteers, not individuals with NAFLD. The hepatic DNL measurement was by overnight labeling for only 12 h, and assessed fasting DNL, not fed or cumulative DNL around the clock. Median DNL was 6.5%, but is much higher in NAFLD (4) and even higher in nonalcoholic steatohepatitis (>40%) (6). This was an outpatient study, so diet and ethanol intake were not controlled. But, as the authors point out, these are real-world settings and are how previous studies that compared blood FA markers were carried out. It looks like there are not yet any easy plasma lipid markers to replace direct measurement of hepatic DNL. But the question deserves continued inquiry. Future studies might focus on subjects with high values for hepatic DNL (individuals with NAFLD, insulin resistance, or type 2 diabetics) or on settings such as fructose or simple sugar intake, and might use longer periods of heavy water labeling. In the meantime, the role of DNL in human metabolism will likely surprise us. And outpatient use of heavy water remains a safe and relatively simple way to measure it. Acknowledgements The sole author was responsible for all aspects of the manuscript. The author reports no conflicts of interest. Notes Abbreviations used: DNL, de novo lipogenesis; FA, fatty acid; NAFLD, nonalcoholic fatty liver disease. References 1. Hirsch J . Fatty acid patterns in human adipose tissue . In: Cahill JF , Renold AE editors. Terjung , R editors. Handbook of Physiology: Adipose Tissue . Washington (DC) : American Physiological Society ; 1965 . p. 181 – 9 .. Reprinted in, editor. Comprehensive physiology; 2011 . 2. Hellerstein MK , Schwarz JM , Neese RA . Regulation of hepatic de novo lipogenesis in humans . Annu Rev Nutr . 1996 ; 16 : 523 – 57 . Google Scholar Crossref Search ADS PubMed 3. Strawford A , Antelo F , Christiansen M , Hellerstein MK . Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O . Am J Physiol Endocrinol Metab . 2004 ; 286 ( 4 ): E577 – 88 . Google Scholar Crossref Search ADS PubMed 4. Lambert JE , Ramos-Roman MA , Browning JD , Parks EJ . Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease . Gastroenterology . 2014 ; 146 ( 3 ): 726 – 35 . Google Scholar Crossref Search ADS PubMed 5. Donnelly KL , Smith CI , Schwarzenberg SJ , Jessurun J , Boldt MD , Parks EJ . Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease . J Clin Invest . 2005 ; 115 ( 5 ): 1343 – 51 . Google Scholar Crossref Search ADS PubMed 6. Lawitz EJ , Coste A , Poordad F , Alkhouri N , Loo N , McColgan BJ , Tarrant JM , Nguyen T , Han L , Chung C et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis . Clin Gastroenterol Hepatol . 2018 ; 16 ( 12 ): 1983 – 91.e3 . Google Scholar Crossref Search ADS PubMed 7. Moon YA , Liang G , Xie X , Frank-Kamenetsky M , Fitzgerald K , Koteliansky V , Brown MS , Goldstein JL , Horton JD . The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals . Cell Metab . 2012 ; 15 ( 2 ): 240 – 6 . Google Scholar Crossref Search ADS PubMed 8. Fabbrini E , Magkos F , Mohammed BS , Pietka T , Abumrad NA , Patterson BW , Okunade A , Klein S . Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity . Proc Natl Acad Sci U S A . 2009 ; 106 ( 36 ): 15430 – 5 . Google Scholar Crossref Search ADS PubMed 9. Stiede K , Miao W , Blanchette HS , Beysen C , Harriman G , Harwood HJ Jr , Kelley H , Kapeller R , Schmalbach T , Westlin WF . Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study . Hepatology . 2017 ; 66 ( 2 ): 324 – 34 . Google Scholar Crossref Search ADS PubMed 10. Lee JJ , Lambert JE , Hovhannisyan Y , Ramos-Roman MA , Trombold JR , Wagner DA , Parks EJ . Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis . Am J Clin Nutr . 2015 ; 101 ( 1 ): 34 – 43 . Google Scholar Crossref Search ADS PubMed 11. Hudgins LC , Hellerstein MK , Seidman CE , Neese RA , Tremaroli JD , Hirsch J . Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects . J Lipid Res . 2000 ; 41 ( 4 ): 595 – 604 . Google Scholar PubMed 12. Rosqvist F , McNeil CA , Pramfalk C , Parry SA , Low WS , Cornfield T , Fielding BA , Hodson L . Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers . Am J Clin Nutr . 2019 ; 109 ( 2 ): In Press . © 2019 American Society for Nutrition. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

American Journal of Clinical NutritionOxford University Press

Published: Feb 1, 2019

References

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