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

• Main Authors: Iroz, Alison, Montagner, Alexandra, Benhamed, Fadila, Levavasseur, Françoise, Polizzi, Arnaud, Anthony, Elodie, Régnier, Marion, Fouché, Edwin, Lukowicz, Céline, Cauzac, Michèle, Tournier, Emilie, Do-Cruzeiro, Marcio, Daujat-Chavanieu, Martine, Gerbal-Chalouin, Sabine, Fauveau, Véronique, Marmier, Solenne, Burnol, Anne-Françoise, Guilmeau, Sandra, Lippi, Yannick, Girard, Jean, Wahli, Walter, Dentin, Renaud, Guillou, Hervé, Postic, Catherine
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2017
• Subjects: ChREBP; FGF21
• Online Access: https://hdl.handle.net/10356/86548; http://hdl.handle.net/10220/44090
• Institution: Nanyang Technological University

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.