1562-P: Hepatic ChREBP-ß Overexpression Enhances Peripheral Glucose and Lipid Homeostasis Independently of FGF21

Abstract

Carbohydrate Response Element-Binding Protein (ChREBP) is a key transcription factor activated by carbohydrate metabolites which transactivates metabolic gene programs involved in the glycolytic and lipogenic response to dietary and circulating sugars. Genetic variants in the ChREBP locus associate with multiple aspects of cardiometabolic disease including dyslipidemia and risk of type 2 diabetes (T2D). Studies overexpressing ChREBP in the liver suggest that ChREBP can play a protective role in preserving glucose and lipid homeostasis. We hypothesized that this protective effect may be mediated through ChREBP’s effect to increase hepatic expression and circulating levels of the beneficial hepatokine, FGF21. To test this hypothesis, we transduced male mice with liver-specific knockout of FGF21 (L-FGF21KO) and lox/lox controls with adenovirus (ADV) containing the constitutively active isoform of murine ChREBP, ChREBP-β, versus ADV-GFP control (N = 4-7 / group). ADV-ChREBP-β transduction induced a 5-fold increase in hepatic (p<0.001) and circulating FGF21 (p<0.0001) in control mice and this was fully abrogated in L-FGF21KO mice. While no significant changes in body weight were detected, ADV-ChREBP-β transduction reduced fasting glycemia and enhanced glucose tolerance in both controls and L-FGF21KO mice. ADV-ChREBP-β transduction induced glycolytic and lipogenic genes similarly in L-FGF21KO and control mice, increased hepatic triglyceride content (3-fold, p<0.005) and induced steatosis, while reducing circulating triglycerides and increasing browning of white adipose tissue. In conclusion, hepatic FGF21 does not mediate the beneficial effect of hepatic ChREBP-β overexpression on peripheral glucose and lipid homeostasis. Disclosure S.Hannou: None. A.Sargsyan: Employee; AstraZeneca. W.Tong: None. J.An: None. C.B.Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk, AstraZeneca. I.Astapova: None. M.A.Herman: Research Support; Eli Lilly and Company. Funding National Institutes of Health (R01DK100425)