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

Christian Bindesbøll, Qiong Fan, Rikke C. Nørgaard, Laura MacPherson, Hai Bin Ruan, Jing Wu, Thomas Pedersen, Knut R. Steffensen, Xiaoyong Yang, Jason Matthews, Susanne Mandrup, Hilde I. Nebb, Line M. Grønning-Wang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)771-785
Number of pages15
JournalJournal of lipid research
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Carbohydrate responsive element-binding protein α
  • Carbohydrate responsive element-binding protein β
  • Chromatin immunoprecipitation
  • Glucose
  • Insulin
  • Lipid metabolism
  • O-linked β-N-acetylglucosamine
  • O-linked β-N-acetylglucosamine transferase

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