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.
Venteclef
Nicolas
N
Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden.
Jakobsson
Tomas
T
Ehrlund
Anna
A
Damdimopoulos
Anastasios
A
Mikkonen
Laura
L
Ellis
Ewa
E
Nilsson
Lisa-Mari
LM
Parini
Paolo
P
Jänne
Olli A
OA
Gustafsson
Jan-Ake
JA
Steffensen
Knut R
KR
Treuter
Eckardt
E
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