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A Specific ChREBP and PPARα 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 alpha (PPAR alpha), 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 alpha knockout mice also demonstrated aPPAR alpha-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 alpha. Our study reports that PPAR alpha is required for the ChREBP-induced glucose response of FGF21.
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Soumis le : mardi 26 mai 2020 - 11:31:32
Dernière modification le : vendredi 9 septembre 2022 - 10:20:08


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Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, et al.. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response. Cell Reports, 2017, 21 (2), pp.403 - 416. ⟨10.1016/j.celrep.2017.09.065⟩. ⟨hal-01837159⟩



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