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

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, Elodie Anthony, Marion Régnier, Edwin Fouché, Céline Lukowicz, Michèle Cauzac, Emilie Tournier, Marcio Do-Cruzeiro, Martine Daujat-Chavanieu, Sabine Gerbal-Chalouin, Véronique Fauveau, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Yannick Lippi, Jean Girard, Walter Wahli, Renaud Dentin, Hervé Guillou, Catherine Postic
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 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 Pparα knockout mice also demonstrated a PPARα-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 PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.

Graphical abstract

Teaser

FGF21 is a hepatokine with beneficial metabolic effects, including control of sucrose preference. Iroz et al. demonstrate that Fgf21 is a unique hepatic gene inducible by both fasting and glucose signals and that the transcription factors PPARα and ChREBP both regulate the endocrine control of sugar intake by hepatic FGF21.


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