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−/−/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.
Highlights
Diets rich in the simple sugars glucose and fructose stimulate hepatic de novo lipogenesis (DNL) and increase circulating triglycerides in humans and rodents [1,2,3,4]
We reported that LXRs are important for nuclear O-GlcNAc signaling, carbohydrate response element-binding protein-α (ChREBPα) O-GlcNAcylation and liver pyruvate-kinase (L-pk) promoter binding activity, and glycogenic and lipogenic gene expression, including expression of the newly discovered Chrebpβ isoform in mouse livers
To examine LXRα-dependent regulation of genes encoding for glucose and fructose metabolizing enzymes in response to fructose and glucose feeding, wild type and LXRα− /− mice were divided into three groups: fasted (24 h), fasted-refed with 60% fructose, or fasted-refed with 60% glucose for 12 h
Summary
Diets rich in the simple sugars glucose and fructose stimulate hepatic de novo lipogenesis (DNL) and increase circulating triglycerides in humans and rodents [1,2,3,4]. Three transcription factors have been identified as important for regulation of lipogenesis: the liver X receptors (LXRα; Nuclear Receptor Subfamily 1 Group H Member 3 (NR1H3) and LXRβ; Nutrients 2017, 9, 678; doi:10.3390/nu9070678 www.mdpi.com/journal/nutrients. 2 Group B (NR2B)) family members to regulate the expression of genes involved in cholesterol homeostasis, lipogenesis, glucose metabolism, and inflammation [6]. In response to dietary cholesterol, glucose, and insulin, hepatic LXRs, in particular LXRα, activate transcription of the two other lipogenic transcription factors SREBP-1c and ChREBPα, which alone or in concert with LXRs induce expression of glycolytic and lipogenic enzymes in hepatic DNL, such as glucokinase (Gk), liver pyruvate kinase (L-pk), ATP citrate lyase (Acl), acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and stearoyl-CoA desaturase-1 (Scd1) [6,8]
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