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

Abstract

SummaryWhile 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.

Intestinal, but not hepatic, ChREBP is required for fructose tolerance

“…Thus, it is likely that hepatic ChREBP in the mouse model reported by Jois et al is not fully ablated. This may explain why canonical ChREBP transcriptional targets were largely unaffected in their putative liver knockouts, in contrast with the data presented here and the data generated by multiple independent labs using global ChREBP-KO mice, which indicate that ChREBP is required for basal expression of many of its metabolic gene targets in vivo (8,11,17,38). Nevertheless, the results of Jois et al are interesting and suggest that different ChREBP isoforms may have distinct physiological and pathophysiological functions.…”

“…We and others have shown that hepatic ChREBP is particularly responsive to fructose consumption and that fructose-mediated activation of ChREBP may contribute to hepatic steatosis, hypertriglyceridemia, and both hepatic and peripheral insulin resistance (10)(11)(12). Recent data indicate that sugaror fructose-mediated activation of ChREBP also regulates secretion of hepatokines like FGF21, which contribute to adaptive metabolic responses to sugar consumption, including regulation of macronutrient preference and progression of NAFLD (13)(14)(15)(16)(17). Confirming the importance of ChREBP to fructose metabolism, whole-body ChREBP-knockout (ChREBP-KO) mice are intolerant to diets containing fructose and become moribund within 1 to 2 weeks (8).…”

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

“…Using the carbohydrate-responsive element-binding protein (ChREBP) −/− and PPAR-α knockout mice, it has been shown that PPAR-α cross-talks with ChREBP, a glucose-sensing lipogenic transcription factor, to regulate fibroblast growth factor (FGF)21 expression. The latter is a hepatokine that improves insulin sensitivity and lipid metabolism and controls the preference for sucrose [24,26]. Sterol regulatory element-binding protein (SREBP)1, which is the insulin-sensing variant of ChREBP, is apart from the liver X receptor, which is also regulated by PPAR-α.…”

“…Using PPAR-δ knockout mice, it could be demonstrated that PPAR-δ exhibits anti-atherogenic properties by reducing very-low density lipoproteins (VLDLs). This is also a consequence from FGF21 signaling [29], which also forms a link to PPAR-α [24,26]. PPAR-δ activation counters angiotensin II-induced adipocyte growth and lipid accumulation.…”

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

“…We have showed recently that a hepatocyte-specific deletion of Ppar induces spontaneous steatosis in aging mice and blunts fasting-induced ketogenesis [18,19]. Moreover PPAR is required for the expression of fibroblast growth factor 21 (FGF21) [42,43], a liver-derived hormone with many endocrine [44] and hepatoprotective effects [45,46].…”