| First Author | Venteclef N | Year | 2010 |
| Journal | Genes Dev | Volume | 24 |
| Issue | 4 | Pages | 381-95 |
| PubMed ID | 20159957 | Mgi Jnum | J:156993 |
| Mgi Id | MGI:4429725 | Doi | 10.1101/gad.545110 |
| Citation | Venteclef N, et al. (2010) GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXR{beta} in the hepatic acute phase response. Genes Dev 24(4):381-95 |
| abstractText | 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. |
