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

  1. Nicolas Venteclef1,
  2. Tomas Jakobsson1,
  3. Anna Ehrlund1,
  4. Anastasios Damdimopoulos1,
  5. Laura Mikkonen2,3,
  6. Ewa Ellis4,
  7. Lisa-Mari Nilsson4,
  8. Paolo Parini4,
  9. Olli A. Jänne2,3,
  10. Jan-Åke Gustafsson1,5,
  11. Knut R. Steffensen1 and
  12. Eckardt Treuter1,6
  1. 1Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden;
  2. 2Biomedicum Helsinki, Institute of Biomedicine (Physiology), University of Helsinki, FI-00014 Helsinki, Finland;
  3. 3Department of Clinical Chemistry, Helsinki University Central Hospital, FI-00290 Helsinki, Finland;
  4. 4Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden;
  5. 5Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA

    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.

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