A Role for Protein Inhibitor of Activated STAT1 (PIAS1) in Lipogenic Regulation through SUMOylation-independent Suppression of Liver X Receptors

Abstract

Liver X receptors (LXRs) are nuclear receptors that function to modulate lipid metabolism as well as immune and inflammatory responses. Upon activation by their ligands, LXRs up-regulate a spectrum of gene transcription programs involved in cholesterol and fatty acid homeostasis. However, the mechanisms by which LXR-mediated transcriptional activation is regulated remain incompletely understood. Here, we show that PIAS1, a member of the protein inhibitor of the activated STAT family of proteins with small ubiquitin-like modifier (SUMO) E3 ligase activity, acts to suppress LXR ligand-dependent transcriptional activation of the lipogenic program in hepatocytes. We found that liver mRNA expression levels of Pias1 and Pias3 were inversely associated with those of genes involved in lipogenesis in mouse models with diet-induced or genetic obesity. Overexpression of PIAS1 in primary hepatocytes resulted in a reduction of LXR ligand-induced fatty acid synthesis and suppression of the expression of lipogenic genes, including Srebp1c and Fas. Moreover, PIAS1 was able to interact with LXRβ and repress its transcriptional activity upon ligand stimulation, which did not require PIAS1-promoted SUMO modification of LXRβ. In addition, PIAS1 could also interact with PGC-1β and attenuate its association with LXRβ, blunting the ability of PGC-1β to co-activate LXRβ. Importantly, PIAS1 impaired LXRβ binding to its target DNA sequence. Taken together, our results suggest that PIAS1 may serve as a lipogenic regulator by negatively modulating LXRs in a SUMOylation-independent manner.