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

作者：Iroz Alison; Montagner Alexandra; Benhamed Fadila; Levavasseur Francoise; Polizzi Arnaud; Anthony Elodie; Regnier Marion; Fouche Edwin; Lukowicz Celine; Cauzac Michele; Tournier Emilie; Do Cruzeiro Marcio; Daujat Chavanieu Martine; Gerbal Chalouin Sabine; Fauveau Veronique; Marmier Solenne; Burnol Anne Francoise; Guilmeau Sandra; Lippi Yannick; Girard Jean; Wahli Walter; Dentin Renaud^*; Guillou Herve^*; Postic Catherine^*

来源：Cell Reports, 2017, 21(2): 403-416.

DOI：10.1016/j.celrep.2017.09.065

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.

• 出版日期2017-10-10