A role for protein inhibitor of activated STAT1 (PIAS1) in lipogenic regulation through SUMOylation-independent suppression of liver X receptors.
J Biol Chem
; 287(45): 37973-85, 2012 Nov 02.
Article
em En
| MEDLINE
| ID: mdl-22969086
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 LXRß and repress its transcriptional activity upon ligand stimulation, which did not require PIAS1-promoted SUMO modification of LXRß. In addition, PIAS1 could also interact with PGC-1ß and attenuate its association with LXRß, blunting the ability of PGC-1ß to co-activate LXRß. Importantly, PIAS1 impaired LXRß 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativação Transcricional
/
Proteínas Inibidoras de STAT Ativados
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Lipogênese
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Receptores Nucleares Órfãos
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article