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Nutrients 2017, 9(7), 678; doi:10.3390/nu9070678

LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice

1
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
2
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
3
Centre for Molecular Medicine Norway, University of Oslo, 0318 Oslo, Norway
4
Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, 0318 Oslo, Norway
5
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S1A8, Canada
*
Authors to whom correspondence should be addressed.
Received: 31 May 2017 / Revised: 15 June 2017 / Accepted: 26 June 2017 / Published: 29 June 2017
(This article belongs to the Special Issue Carbohydrate Metabolism in Health and Disease)
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Abstract

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−/−−/−) 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. View Full-Text
Keywords: LXR; ChREBP; de novo lipogenesis (DNL); O-GlcNAc LXR; ChREBP; de novo lipogenesis (DNL); O-GlcNAc
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Fan, Q.; Nørgaard, R.C.; Bindesbøll, C.; Lucas, C.; Dalen, K.T.; Babaie, E.; Itkonen, H.M.; Matthews, J.; Nebb, H.I.; Grønning-Wang, L.M. LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice. Nutrients 2017, 9, 678.

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