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LXR? Regulates Hepatic ChREBP? Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.

ABSTRACT: Liver X receptors (LXR?/?) and carbohydrate response element-binding proteins (ChREBP?/?) are key players in the transcriptional control of hepatic de novo lipogenesis. LXR?/? double knockout (LXR?^-/-/?^-/-) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBP? activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXR? knockout (LXR?^-/-) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXR?^-/- mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebp?, indicating reduced ChREBP? activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXR?^-/- mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXR?, suggesting a role for LXR? in regulating ChREBP? activity upon fructose feeding. In conclusion, we propose that LXR? is an important regulator of hepatic lipogenesis and ChREBP? activity upon glucose, but not fructose feeding in mice.

SUBMITTER: Fan Q

PROVIDER: S-EPMC5537793 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.

Fan Qiong Q Nørgaard Rikke C RC Bindesbøll Christian C Lucas Christin C Dalen Knut Tomas KT Babaie Eshrat E Itkonen Harri M HM Matthews Jason J Nebb Hilde I HI Grønning-Wang Line M LM

Nutrients 20170629 7

Liver X receptors (LXRα/β) and carbohydrate response element-binding proteins (ChREBPα/β) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRα/β double knockout (LXRα-/-/β-/-) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPα activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthes ...[more]

PMID: 28661453

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Project description:ObjectiveIncreased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.MethodsWe tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.ResultsHepatic expression of ChREBP-? and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-? and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.ConclusionsIn summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

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LXR? Regulates Hepatic ChREBP? Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.

Publications

LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.

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