GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRβ in the hepatic acute phase response

Nicolas Venteclef, Tomas Jakobsson, Anna Ehrlund, Anastasios Damdimopoulos, Laura Mikkonen, Ewa Ellis, Lisa Mari Nilsson, Paolo Parini, Olli A. Jänne, Jan Åke Gustafsson, Knut R. Steffensen, Eckardt Treuter

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

The orphan receptor LRH-1 and the oxysterol receptors LXRα and LXRβ are established transcriptional regulators of lipid metabolism that appear to control inflammatory processes. Here, we investigate the anti-inflammatory actions of these nuclear receptors in the hepatic acute phase response (APR). We report that selective synthetic agonists induce SUMOylation-dependent recruitment of either LRH-1 or LXR to hepatic APR promoters and prevent the clearance of the N-CoR corepressor complex upon cytokine stimulation. Investigations of the APR in vivo, using LXR knockout mice, indicate that the anti-inflammatory actions of LXR agonists are triggered selectively by the LXRβ subtype. We further find that hepatic APR responses in small ubiquitin-like modifier-1 (SUMO-1) knockout mice are increased, which is due in part to diminished LRH-1 action at APR promoters. Finally, we provide evidence that the metabolically important coregulator GPS2 functions as a hitherto unrecognized transrepression mediator of interactions between SUMOylated nuclear receptors and the N-CoR corepressor complex. Our study extends the knowledge of anti-inflammatory mechanisms and pathways directed by metabolic nuclear receptor-corepressor networks to the control of the hepatic APR, and implies alternative pharmacological strategies for the treatment of human metabolic diseases associated with inflammation.

Original languageEnglish (US)
Pages (from-to)381-395
Number of pages15
JournalGenes and Development
Volume24
Issue number4
DOIs
StatePublished - Feb 15 2010

Keywords

  • Acute phase response
  • GPS2
  • Liver inflammation
  • LRH-1
  • LXR

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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