Rhee James, Ge Hongfei, Yang Wenli, Fan Melina, Handschin Christoph, Cooper Marcus, Lin Jiandie, Li Cai, Spiegelman Bruce M
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA.
J Biol Chem. 2006 May 26;281(21):14683-90. doi: 10.1074/jbc.M512636200. Epub 2006 Mar 29.
Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator involved in several aspects of energy metabolism. It is induced or activated under different stimuli in a highly tissue-specific manner and subsequently partners with certain transcription factors in those tissues to execute various biological programs. In the fasted liver, PGC-1alpha is induced and interacts with hepatocyte nuclear factor 4alpha (HNF4alpha) and other transcription factors to activate gluconeogenesis and increase hepatic glucose output. Given the broad spectrum of liver genes responsive to HNF4alpha, we sought to determine those that were specifically targeted by the combination of PGC-1alpha and HNF4alpha. Coexpression of these two molecules in murine stem cells reveals a high induction of mRNA for apolipoproteins A-IV and C-II. Forced expression of PGC-1alpha in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III. Coactivation of the apoC-III/A-IV promoter region by PGC-1alpha occurs through a highly conserved HNF4alpha response element, the loss of which completely abolishes activation by PGC-1alpha and HNF4alpha. Adenoviral infusion of PGC-1alpha into live mice increases hepatic expression of apolipoproteins A-IV, C-II, and C-III and increases serum and very low density lipoprotein triglyceride levels. Conversely, knock down of PGC-1alpha in vivo causes a decrease in both apolipoprotein expression and serum triglyceride levels. These data point to a crucial role for the PGC-1alpha/HNF4alpha partnership in hepatic lipoprotein metabolism.
过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）是一种参与能量代谢多个方面的转录辅激活因子。它在不同刺激下以高度组织特异性的方式被诱导或激活，随后在这些组织中与某些转录因子结合，以执行各种生物学程序。在禁食的肝脏中，PGC-1α被诱导并与肝细胞核因子4α（HNF4α）及其他转录因子相互作用，以激活糖异生并增加肝脏葡萄糖输出。鉴于对HNF4α有反应的肝脏基因范围广泛，我们试图确定那些被PGC-1α和HNF4α组合特异性靶向的基因。这两种分子在小鼠干细胞中的共表达显示载脂蛋白A-IV和C-II的mRNA有高度诱导。在小鼠和人类肝癌细胞中强制表达PGC-1α会增加与极低密度脂蛋白和甘油三酯代谢相关的一部分载脂蛋白的mRNA，包括载脂蛋白A-IV、C-II和C-III。PGC-1α对载脂蛋白C-III/A-IV启动子区域的共激活通过一个高度保守的HNF4α反应元件发生，该元件的缺失完全消除了PGC-1α和HNF4α的激活作用。将PGC-1α腺病毒注入活体小鼠会增加肝脏中载脂蛋白A-IV、C-II和C-III的表达，并增加血清和极低密度脂蛋白甘油三酯水平。相反，在体内敲低PGC-1α会导致载脂蛋白表达和血清甘油三酯水平降低。这些数据表明PGC-1α/HNF4α组合在肝脏脂蛋白代谢中起关键作用。
