Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid.
Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid.
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DOI：
10.1016/j.cmet.2010.09.001
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发表时间：
2010-10-06
期刊：
影响因子：
29
通讯作者：
Lin JD
中科院分区：
文献类型：
--
作者：
Hernandez C;Molusky M;Li Y;Li S;Lin JD
过氧化物酶体增殖物激活受体γ共激活因子-1 β（PGC-1β）是一种转录共激活因子，通过激活肝脏脂肪生成和脂蛋白分泌诱导高脂血症。PGC-1β的表达受游离脂肪酸的调节。我们发现PGC-1β通过刺激载脂蛋白C3（APOC 3）表达和升高循环中APOC 3水平来调节血浆甘油三酯代谢。值得注意的是，肝脏特异性敲低APOC 3显著改善了小鼠中PGC-1β诱导的高脂血症。PGC-1β和APOC 3的肝脏表达在烟酸（一种广泛用于降低血浆甘油三酯的处方药）急性和慢性治疗后降低。腺病毒介导的肝脏中PGC-1β或APOC 3的敲低重现了烟酸的降血脂作用。肝脏PGC-1β转录复合物的蛋白质组学分析表明，它通过共激活孤儿核受体ERRα和招募染色质重塑辅因子来刺激APOC 3表达。总之，这些研究确定PGC-1β是APOC 3基因簇的重要调节因子，并揭示了烟酸实现其治疗作用的机制。
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.
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与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
15.9
作者：
Benyó, Z;Gille, A;Offermanns, S
通讯作者：
Offermanns, S
影响因子：
64.5
作者：
Lin, JD;Wu, PH;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
4.8
作者：
Carrier, JC;Deblois, GV;Giguère, V
通讯作者：
Giguère, V
影响因子：
29
作者：
Li, Sinning;Liu, Chang;Li, Na;Hao, Tong;Han, Ting;Hill, David E.;Vidal, Marc;Lin, Jiandie D.
通讯作者：
Lin, Jiandie D.