HGFAC Is a ChREBP-Regulated Hepatokine That Enhances Glucose and Lipid Homeostasis

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates metabolic gene programs. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating triglycerides (TG). The transcriptional targets that mediate its pleiotropic physiological effects are poorly understood. To identify novel ChREBP-regulated hepatokines that contribute to its effects on metabolism, we integrated ChIP-seq for ChREBP in mouse liver with human GWAS data for TGs and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising candidate. HGFAC is a circulating zymogen that activates Hepatocyte Growth Factor (HGF), a multifunction cytokine involved in cellular growth, motility, and morphogenesis. High fructose feeding increased circulating HGFAC by 1.8-fold (p<0.001) and this was abrogated in liver specific ChREBP KO mice. Similar increases were seen in mice fed high sucrose/high fat diet and in obese Zucker rats (2.6-fold, p<0.001). In humans, expression of hepatic ChREBP transcriptional targets associated with HGFAC expression (Pearson r= 0.66, p <0.0001), and its expression was elevated in patients with obesity and T2D (2.7-fold, p<0.001). Putative loss of function variants in HGFAC associated with hypertriglyceridemia in humans, and deletion of HGFAC in mice increased circulating TGs (1.4-fold, p<0.005), and caused glycerol and glucose intolerance despite a 40% reduction in hepatic TG content (p<0.001). RNA-seq indicated that HGFAC regulates hepatic metabolism through modulation of hepatic PPARG expression. Reciprocal effects on PPARG expression and metabolic phenotypes were observed following adenovirus HGFAC overexpression in mice. Moreover, HGF induces PPARG express 1.3-fold in HepG2 cells (p<0.0001). In conclusion, ChREBP responds to carbohydrate overnutrition and regulates systemic glucose and lipid metabolism via an HGFAC-HGF-PPARG signaling axis. Disclosure A. Sargsyan: None. I. Astapova: None. L. T. Tsai: None. M. A. Herman: Research Support; Self; Eli Lilly and Company. L. Doridot: Employee; Spouse/Partner; Eli Lilly and Company. S. A. Hannou: None. W. Tong: None. H. Srinivasan: None. R. Ivison: None. R. Monn: None. H. H. Kou: None. J. Haldeman: None. Funding American Diabetes Association (1-19-PDF-088 to A.S.)