Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis
Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis
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DOI：
10.1152/ajpgi.00080.2005
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发表时间：
2006-01-01
影响因子：
4.5
通讯作者：
Sievert, W
中科院分区：
文献类型：
--
作者：
Patella, S;Phillips, DJ;Sievert, W
激活素 A 是转化生长因子-β 超家族的成员，在肝细胞中组成型表达，并通过强直性抑制肝细胞 DNA 合成来调节肝脏质量。卵泡抑素是激活素生物活性的主要生物抑制剂。这些分子可能参与肝纤维形成，但其具体作用仍不清楚。我们研究了培养的大鼠肝星状细胞 (HSC) 和给予 CCl4 8 周的大鼠中的激活素和卵泡抑素基因和蛋白表达，并检查了卵泡抑素给药对肝纤维化发展的影响。在活化的 HSC 中，激活素 mRNA 上调且表达水平较高，而卵泡抑素 mRNA 表达与基线相比没有变化。正常小叶肝细胞中的激活素 A 表达重新分布到纤维化肝脏中的间隔周肝细胞和平滑肌肌动蛋白阳性 HSC。在接受卵泡抑素治疗的 CCl4 暴露大鼠中，纤维化减少了 32%，在第 4 周达到最大。在卵泡抑素治疗期间，肝细胞凋亡减少了 87%，并在第 4 周达到最大。总之，激活素是由体外和体内激活的 HSC 产生的。 HSC 中卵泡抑素基因表达没有同时上调表明 HSC 衍生的激活素具有生物活性并且不会受到卵泡抑素的对抗。我们的体内和体外结果表明，激活素介导的事件有助于肝纤维发生，而卵泡抑素通过限制 HSC 增殖和抑制肝细胞凋亡来减弱纤维发生的早期事件。
Activin A, a member of the transforming growth factor-beta superfamily, is constitutively expressed in hepatocytes and regulates liver mass through tonic inhibition of hepatocyte DNA synthesis. Follistatin is the main biological inhibitor of activin bioactivity. These molecules may be involved in hepatic fibrogenesis, although defined roles remain unclear. We studied activin and follistatin gene and protein expression in cultured rat hepatic stellate cells (HSCs) and in rats given CCl4 for 8 wk and examined the effect of follistatin administration on the development of hepatic fibrosis. In activated HSCs, activin mRNA was upregulated with high expression levels, whereas follistatin mRNA expression was unchanged from baseline. Activin A expression in normal lobular hepatocytes redistributed to periseptal hepatocytes and smooth muscle actin-positive HSCs in the fibrotic liver. A 32% reduction in fibrosis, maximal at week 4, occurred in CCl4-exposed rats treated with follistatin. Hepatocyte apoptosis decreased by 87% and was maximal at week 4 during follistatin treatment. In conclusion, activin is produced by activated HSCs in vitro and in vivo. Absence of simultaneous upregulation of follistatin gene expression in HSCs suggests that HSC-derived activin is biologically active and unopposed by follistatin. Our in vivo and in vitro results demonstrate that activin-mediated events contribute to hepatic fibrogenesis and that follistatin attenuates early events in fibrogenesis by constraining HSC proliferation and inhibiting hepatocyte apoptosis.