title: Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid.
abstract: Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β 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-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β 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-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Molusky
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Yaqiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.affiliation: Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address: jdlin@umich.edu.
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009525:Niacin / Q000494:pharmacology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D053305:Apolipoprotein C-III; D000960:Hypolipidemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D009525:Niacin