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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.

ABSTRACT: Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

SUBMITTER: Lanaspa MA

PROVIDER: S-EPMC3833672 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.

Lanaspa Miguel A MA Ishimoto Takuji T Li Nanxing N Cicerchi Christina C Orlicky David J DJ Ruzycki Philip P Rivard Christopher C Inaba Shinichiro S Roncal-Jimenez Carlos A CA Bales Elise S ES Diggle Christine P CP Asipu Aruna A Petrash J Mark JM Kosugi Tomoki T Maruyama Shoichi S Sanchez-Lozada Laura G LG McManaman James L JL Bonthron David T DT Sautin Yuri Y YY Johnson Richard J RJ

Nature communications 20130101

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy in ...[more]

PMID: 24022321

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Project description:Non-alcohol fatty liver disease (NAFLD) is a common disorder that has increased in prevalence 20-fold over the last three decades. It covers a spectrum of conditions resulting from excess lipid accumulation in the liver without alcohol abuse. Among all the risk factors, over-consumption of fructose has been repeatedly reported in both clinical and experimental studies to be highly associated with the development of NAFLD. However, studying in vivo systems is complicated, time consuming and expensive. A detailed kinetic model of fructose metabolism was constructed to investigate the metabolic mechanisms whereby fructose consumption can induce dyslipidaemia associated with NAFLD and to explore whether the pathological conditions can be reversed during the early stages of disease. The model contains biochemical components and reactions identified from the literature, including ~120 parameters, 25 variables, and 25 first order differential equations. Three scenarios were presented to demonstrate the behavior of the model. Scenario one predicts the acute effects of a change in carbohydrate input in lipid profiles. The results present progressive triglyceride accumulations in the liver and plasma for three diets. The rate of accumulation was greater in the fructose diet than that of the mixed or glucose only models. Scenario two explores the variability of metabolic reaction rate within the general population. Sensitivity analysis reveals that hepatic triglyceride concentration is most sensitive to the rate constant of pyruvate kinase and fructokinase. Scenario three tests the effect of one specific inhibitor that might be potentially administered. The simulations of fructokinase suppression provide a good model for potentially reversing simple steatosis induced by high fructose consumption, which can be corroborated by experimental studies. The predictions in these three scenarios suggest that the model is robust and it has sufficient detail to present the kinetic relationship between fructose and lipid in the liver.

Project description:ObjectiveThe risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.MethodsWT, IL-4Rα-deficient (IL-4Rα-/-) and STAT6-deficient mice (STAT6-/-) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.ResultsWe show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.ConclusionOur findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.

Dataset Information

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.

Publications

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.

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