Format

Send to

Choose Destination
J Lipid Res. 2015 Apr;56(4):771-85. doi: 10.1194/jlr.M049130. Epub 2015 Feb 27.

Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity.

Author information

1
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
2
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
3
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06519 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519.
4
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
5
Division of Clinical Chemistry Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, C174, SE-141 86 Stockholm, Sweden.
6
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06519 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519.
7
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.

Abstract

Liver X receptor (LXR)α and LXRβ play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element-binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene expression in vivo, we subjected control and streptozotocin-treated LXRα/β(+/+) and LXRα/β(-/-) mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPβ. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK expression, nuclear O-GlcNAc signaling, and ChREBP expression and activity.

KEYWORDS:

O-linked β-N-acetylglucosamine; O-linked β-N-acetylglucosamine transferase; carbohydrate responsive element-binding protein α; carbohydrate responsive element-binding protein β; chromatin immunoprecipitation; glucose; insulin; lipid metabolism

PMID:
25724563
PMCID:
PMC4373736
DOI:
10.1194/jlr.M049130
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center