LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice.
Liver X receptors (LXRα/β) and carbohydrate response element-binding proteins (ChREBPα/β) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRα/β double knockout (LXRα-/-/β-/-) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPα 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 LXRα knockout (LXRα-/-) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXRα-/- mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebpβ, indicating reduced ChREBPα activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXRα-/- mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXRβ, suggesting a role for LXRβ in regulating ChREBPα activity upon fructose feeding. In conclusion, we propose that LXRα is an important regulator of hepatic lipogenesis and ChREBPα activity upon glucose, but not fructose feeding in mice.
['Fan|Qiong|Q|', 'Nørgaard|Rikke C|RC|', 'Bindesbøll|Christian|C|', 'Lucas|Christin|C|', 'Dalen|Knut Tomas|KT|', 'Babaie|Eshrat|E|', 'Itkonen|Harri M|HM|', 'Matthews|Jason|J|', 'Nebb|Hilde I|HI|', 'Grønning-Wang|Line M|LM|']
D000821:Animal Feed D000824:Animal Nutritional Physiological Phenomena D000818:Animals D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors D004032:Diet D005508:Food Deprivation D005632:Fructose D005786:Gene Expression Regulation D005947:Glucose D050155:Lipogenesis D000071518:Liver X Receptors D051379:Mice D018345:Mice, Knockout D009687:Nuclear Proteins D015398:Signal Transduction D051780:Sterol Regulatory Element Binding Protein 1 D014157:Transcription Factors
O-GlcNAc LXR ChREBP de novo lipogenesis (DNL)