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A Specific ChREBP and PPAR? Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.

ABSTRACT: While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor ? (PPAR?), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp-/- mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp-/- mice. Unexpectedly, carbohydrate challenge of hepatic Ppar? knockout mice also demonstrated a PPAR?-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPAR?. Our study reports that PPAR? is required for the ChREBP-induced glucose response of FGF21.

SUBMITTER: Iroz A

PROVIDER: S-EPMC5643524 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.

Iroz Alison A Montagner Alexandra A Benhamed Fadila F Levavasseur Françoise F Polizzi Arnaud A Anthony Elodie E Régnier Marion M Fouché Edwin E Lukowicz Céline C Cauzac Michèle M Tournier Emilie E Do-Cruzeiro Marcio M Daujat-Chavanieu Martine M Gerbal-Chalouin Sabine S Fauveau Véronique V Marmier Solenne S Burnol Anne-Françoise AF Guilmeau Sandra S Lippi Yannick Y Girard Jean J Wahli Walter W Dentin Renaud R Guillou Hervé H Postic Catherine C

Cell reports 20171001 2

While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis i ...[more]

PMID: 29020627

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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.

Dataset Information

A Specific ChREBP and PPAR? Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.

Publications

A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.

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