GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response.
The orphan receptor LRH-1 and the oxysterol receptors LXRalpha and LXRbeta 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 LXRbeta 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.
Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden.
Nicolas
N
Venteclef
Tomas
T
Jakobsson
Anna
A
Ehrlund
Anastasios
A
Damdimopoulos
Laura
L
Mikkonen
Ewa
E
Ellis
Lisa-Mari
LM
Nilsson
Paolo
P
Parini
Olli A
OA
Jänne
Jan-Ake
JA
Gustafsson
Knut R
KR
Steffensen
Eckardt
E
Treuter
D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000276:immunology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000276:immunology*
D000893:Anti-Inflammatory Agents; C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C082631:NR5A2 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D025841:Small Ubiquitin-Related Modifier Proteins