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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Acylation / drug effects
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Eating
  • Fasting
  • Gene Expression Regulation / drug effects
  • Glucose / pharmacology
  • Humans
  • Lipogenesis / drug effects
  • Liver / cytology*
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism*
  • Liver X Receptors
  • Male
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Orphan Nuclear Receptors / deficiency
  • Orphan Nuclear Receptors / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport / drug effects
  • Pyruvate Kinase / metabolism
  • Signal Transduction* / drug effects
  • Streptozocin / adverse effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation / drug effects
  • Triglycerides / biosynthesis
  • Triglycerides / blood

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Liver X Receptors
  • Mlxipl protein, mouse
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Nuclear Proteins
  • Orphan Nuclear Receptors
  • Protein Isoforms
  • Transcription Factors
  • Triglycerides
  • Streptozocin
  • Pyruvate Kinase
  • Glucose
  • Acetylglucosamine