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

Yongliang Zhang,Luting Zhou,Liu Yang,Hao Ying,Jia Li,Ping Huang,Xiaomeng Jiang,Jingya Li,Zhenji Gan,Weiping J Zhang,Mengle Shao,Yong Liu,Ting Mao,Yan Chen,Meina Cao

doi:10.1074/jbc.m112.403139

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.

Highlights

PIAS proteins are implicated in the regulation of many transcription factors through distinct mechanisms
Expression of Hepatic Pias1 and Pias3 Is Inversely Correlated with That of Lipogenic Genes in Obese Mice—To gain insights into the possible metabolic actions of PIAS proteins, we first tested by quantitative RT-PCR analysis whether hepatic Pias1 and Pias3 genes exhibit altered expression patterns in the states of obesity
This HFDinduced up-regulation of Pias1 and Pias3 was paralleled with marked reductions in the mRNA abundance of Srebp1c and the lipogenic enzymes Acc1, Fas, and Scd1 (Fig. 1A), consistent with our previous finding that HFD feeding resulted in suppressed expression of lipogenic genes [34]

Summary

Background

PIAS proteins are implicated in the regulation of many transcription factors through distinct mechanisms. Lee et al [21] demonstrated that in IFN-␥-stimulated brain astrocytes, both synthetic and oxysterol derivatives of LXR ligands could suppress STAT1-dependent inflammatory responses; this action requires SUMOylation of LXR␤ and LXR␣, which were catalyzed by two SUMO E3 ligase family members, the protein inhibitor of activated STAT1 (PIAS1) and histone diacetylase 4 (HDAC4), respectively. PIAS proteins have recently been shown to have SUMO E3 ligase activity [25, 26] and are implicated in regulation of many transcription factors by distinct mechanisms such as promoting protein SUMOylation, blocking the DNA binding ability of transcription factors, or recruiting transcriptional co-repressors or coactivators [24, 27] They are well documented to play crucial roles in the regulation of gene activation pathways in inflammation and immunity, it is largely unclear whether PIAS proteins can exert metabolic functions by modulating gene transcription programs involved in lipid homeostasis. We found a repressive effect of PIAS1 upon LXR ligand-stimulated up-regulation of lipogenic genes and attempted to decipher the molecular basis of PIAS1 actions in the LXR-dependent control of the lipogenic program

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION