Wang Xuemin, Tang Xiaoli, Gong Xiaoming, Albanis Efsevia, Friedman Scott L, Mao Zixu
Liver Research Center, Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence 02903, USA.
Gastroenterology. 2004 Oct;127(4):1174-88. doi: 10.1053/j.gastro.2004.07.007.
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcriptional regulation plays a key role in this process. We studied the role of transcription factor myocyte enhancer factor 2 (MEF2) during HSC activation.
Culture of HSCs isolated from rat liver on plastic dishes and HSC-T6 on a basement membrane-like matrix were used as models of HSC activation and deactivation, respectively. The expression and activity of MEF2 were correlated with HSC activation. The roles of MEF2 during HSC activation were assessed in vitro and in vivo by animal models of fibrosis.
Early induction of MEF2 messenger RNA and protein accompanied culture-induced HSC activation. This was associated with enhanced MEF2 DNA binding and transactivation activity. p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase pathway was required for increased MEF2 activity during HSC activation. Increased MEF2 protein also correlated with fibrosis in vivo. Reversal of HSC activation was paralleled by a marked decrease in MEF2 protein and activity. Functionally, enhancing MEF2 significantly increased the expression of alpha-smooth muscle actin (alpha-SMA), activated collagen I promoter activity, and stimulated HSC proliferation. MEF2 interference RNA significantly inhibited expression of alpha-SMA, collagen alpha1(I), and proliferating cell nuclear antigen.
The studies provide the first evidence for the presence of MEF2 in the liver and show that MEF2 regulates multiple aspects of HSC activation. These studies show a novel role of MEF2 as a key nuclear mediator that may participate in the pathologic process of liver fibrogenesis in vivo.
肝星状细胞（HSCs）在肝纤维化发展过程中会发生激活。转录调控在此过程中起关键作用。我们研究了转录因子肌细胞增强因子2（MEF2）在肝星状细胞激活过程中的作用。
分别将从大鼠肝脏分离的肝星状细胞在塑料培养皿上培养以及将肝星状细胞系HSC-T6在类基底膜基质上培养，作为肝星状细胞激活和失活的模型。MEF2的表达和活性与肝星状细胞激活相关。通过纤维化动物模型在体外和体内评估MEF2在肝星状细胞激活过程中的作用。
MEF2信使核糖核酸和蛋白质的早期诱导伴随着培养诱导的肝星状细胞激活。这与增强的MEF2 DNA结合和反式激活活性相关。在肝星状细胞激活过程中，MEF2活性增加需要p38丝裂原活化蛋白激酶而非细胞外信号调节激酶途径。MEF2蛋白增加也与体内纤维化相关。肝星状细胞激活的逆转与MEF2蛋白和活性的显著降低平行。在功能上，增强MEF2可显著增加α-平滑肌肌动蛋白（α-SMA）的表达，激活I型胶原启动子活性，并刺激肝星状细胞增殖。MEF2干扰RNA显著抑制α-SMA、I型胶原α1（I）和增殖细胞核抗原的表达。
这些研究首次证明了MEF2在肝脏中的存在，并表明MEF2调节肝星状细胞激活多个方面。这些研究显示了MEF作为一种关键核介质的新作用，其可能参与体内肝纤维化形成的病理过程。
