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首页> 外文期刊>Cell metabolism >Regulation of hepatic ApoC3 expression by PGC-1beta mediates hypolipidemic effect of nicotinic acid.
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Regulation of hepatic ApoC3 expression by PGC-1beta mediates hypolipidemic effect of nicotinic acid.

机译：PGC-1beta对肝脏ApoC3表达的调节介导了烟酸的降血脂作用。

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摘要

Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1beta (PGC-1beta) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1beta is regulated by free fatty acids. Here we show that PGC-1beta 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-1beta-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1beta 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-1beta or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1beta transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRalpha and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1beta as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.
机译：过氧化物酶体增殖物激活受体（PPAR）γ共激活因子1beta（PGC-1beta）是一种转录共激活因子，它通过激活肝脏脂肪生成和脂蛋白分泌，响应于饮食脂肪而诱导高甘油三酯血症。 PGC-1beta的表达受游离脂肪酸的调节。在这里，我们显示PGC-1beta通过刺激载脂蛋白C3（APOC3）表达并提高循环中的APOC3水平来调节血浆甘油三酸酯的代谢。值得注意的是，APOC3的肝脏特异性敲低显着改善了PGC-1beta诱导的小鼠高甘油三酯血症。响应于烟酸的急慢性治疗，PGC-1beta和APOC3的肝表达降低，烟酸是一种广泛使用的降低血浆甘油三酯的药物。腺病毒介导的PGC-1beta或APOC3在肝脏中的敲低可概括烟酸的降血脂作用。肝PGC-1beta转录复合物的蛋白质组学分析表明，它通过共同激活孤儿核受体ERRalpha和募集染色质重塑辅因子来刺激APOC3表达。总之，这些研究确定PGC-1beta是APOC3基因簇的重要调节剂，并揭示了烟酸通过其实现治疗效果的机制。

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