Lxr Alpha Regulates Hepatic Chrebp Alpha Activity And Lipogenesis Upon Glucose, But Not Fructose Feeding In Mice

Liver X receptors (LXR alpha/beta) and carbohydrate response element-binding proteins (ChREBP alpha/beta) are key players in the transcriptional control of hepatic de novo lipogenesis. LXR alpha/beta double knockout (LXR alpha(-/-)/beta(-/-)) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBP alpha 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 alpha knockout (LXR alpha(-/-)) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXR alpha(-/-) mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebp beta, indicating reduced ChREBP alpha activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXR alpha(-/-) mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXR beta, suggesting a role for LXR beta in regulating ChREBP alpha activity upon fructose feeding. In conclusion, we propose that LXR alpha is an important regulator of hepatic lipogenesis and ChREBP alpha activity upon glucose, but not fructose feeding in mice.