LXR? Regulates Hepatic ChREBP? Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.

ABSTRACT: Liver X receptors (LXR?/?) and carbohydrate response element-binding proteins (ChREBP?/?) are key players in the transcriptional control of hepatic de novo lipogenesis. LXR?/? double knockout (LXR?^-/-/?^-/-) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBP? activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXR? knockout (LXR?^-/-) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXR?^-/- mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebp?, indicating reduced ChREBP? activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXR?^-/- mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXR?, suggesting a role for LXR? in regulating ChREBP? activity upon fructose feeding. In conclusion, we propose that LXR? is an important regulator of hepatic lipogenesis and ChREBP? activity upon glucose, but not fructose feeding in mice.

SUBMITTER: Fan Q 

PROVIDER: S-EPMC5537793 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature