Regulation of hepatic ApoC3 expression by PGC-1? mediates hypolipidemic effect of nicotinic acid.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) ? coactivator-1? (PGC-1?) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1? is regulated by free fatty acids. Here we show that PGC-1? regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1?-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1? and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1? or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1? transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERR? and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1? as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.

SUBMITTER: Hernandez C 

PROVIDER: S-EPMC2950832 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature