Fructose consumption in humans and animals has been linked to enhanced de novo lipogenesis, dyslipidemia and insulin resistance. Hereditary deficiency of Ketohexokinase (KHK), the first enzymatic step in fructose metabolism, leads to essential fructosuria in humans, characterized by elevated levels of blood and urinary fructose following fructose ingestion, but is otherwise clinically benign. To address whether KHK deficiency is associated with altered glucose and lipid metabolism, a KHK knockout (KO) mouse line was generated and characterized. NMR spectroscopic analysis of plasma following ingestion of [6-13C] fructose revealed striking differences in biomarkers of fructose metabolism. Significantly elevated urine and plasma 13C-fructose levels were observed in KHK KO vs wild-type (WT) control mice, as was reduced conversion of 13C-fructose into plasma 13C-glucose and 13C-lactate. KHK KO mice on a standard chow diet displayed no metabolic abnormalities with respect to ambient glucose, glucose tolerance, body weight, food intake, and circulating trigylcerides, β-hydroxybutyrate, and lactate. When placed on a high fat and high fructose (HF/HFruc) diet, KHK KO mice displayed a transient initial reduction in body weight and glucose levels, after which a progressive hyperphagia led to normalization of body weight. KHK KO mice also had markedly reduced liver weight, triglyceride levels, and insulin levels following the dietary challenge, consistent with improved insulin sensitivity. Together, these results suggest that KHK KO mice may serve as a good model for essential fructosuria in humans, and that inhibition of KHK offers the potential to protect from diet-induced hepatic steatosis and insulin resistance.
AJP - Endocrinology and Metabolism – The American Physiological Society
Published: Jan 24, 2018
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