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

Abstract

The orphan receptor LRH-1 and the oxysterol receptors LXRa and LXRb 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 LXRb 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.[Keywords: LRH-1; LXR; GPS2; acute phase response; liver inflammation] Supplemental material is available at http://www.genesdev.org.

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A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4

“…As shown in Fig. 6, knockdown of endogenous SUMO-1 by a dual siRNA mixture commonly used to specifically deplete SUMO-1 (79,80) led to a significant reduction in the ability of KLF4 to transactivate both the C/EBP␤ and Lefty1 promoters compared with controls (Fig. 6, A and B).…”

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