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

• Published in: Cell reports (Cambridge) 2017-10, Vol.21 (2), p.403-416
• 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
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; ChREBP; Female; FGF21; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Glucose - metabolism; glucose intake; Hepatocytes - metabolism; Life Sciences; Male; Mice; Mice, Inbred C57BL; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PPAR alpha - genetics; PPAR alpha - metabolism; PPARα; Response Elements; sucrose preference; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• 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 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. [Display omitted] •Fgf21 is a unique hepatic gene inducible by both catabolic and anabolic signals•The ChREBP-mediated induction of Fgf21 in hepatocytes requires PPARα•Loss of PPARα impairs Fgf21 promoter accessibility at the ChoRE•PPARα is required for the control of sucrose preference in vivo 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.