Histone Deacetylase Inhibition Suppresses the Transforming Growth Factor β1-Induced Epithelial-to-Mesenchymal Transition in Hepatocytes
Histone Deacetylase Inhibition Suppresses the Transforming Growth Factor β1-Induced Epithelial-to-Mesenchymal Transition in Hepatocytes
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DOI：
10.1002/hep.23765
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发表时间：
2010-09-01
期刊：
影响因子：
13.5
通讯作者：
Koteish, Ayman A.
中科院分区：
文献类型：
--
作者：
Kaimori, Aki;Potter, James J.;Koteish, Ayman A.
转化生长因子β1（TGFβ1）在诱导肝细胞上皮间质转化（EMT）方面发挥着至关重要的作用，这有助于肝纤维化的发病机制。抑制 TGF beta 1 级联可抑制 EMT 和由此产生的纤维化。在本研究中，我们重点关注 EMT 诱导的肝细胞纤维化和 I 型胶原基因的表观遗传调控。组蛋白乙酰化是调节基因转录的重要、主要的表观遗传机制。我们评估了 α 小鼠肝脏 12 肝细胞（一种土亚型小鼠细胞系）中 I 型胶原的表观遗传调控，这些细胞在用 TGF beta 1 处理后经历了 EMT。组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 抑制 EMT；这反映在上皮标记物和功能（E-钙粘蛋白和白蛋白）的保留上。纤维化是 EMT 的最终结果，但已被 TSA 废除； I 型胶原沉积的抑制表明了这一点。 TSA 通过使母亲对十肢麻痹同源物 3 (Smad3)/Smad4 转录复合物失活并干扰 I 型胶原蛋白启动子的共激活因子 p300 并阻止其与 Smad3 结合来发挥其抗 EMT 作用。 TSA 还恢复了 Friend 白血病病毒整合 1，这是 I 型胶原蛋白基因的抑制剂。 TGFβ1 诱导的 EMT 及其 TSA 的抑制作用在人原代肝细胞中得到了复制。结论：组蛋白脱乙酰酶抑制消除了肝细胞中 TGFβ1 诱导的 EMT，并通过 I 型胶原的表观遗传调节逆转 EMT 诱导的纤维化。 （肝病学 2010；52：1033-1045）
Transforming growth factor beta 1 (TGF beta 1) plays a crucial role in the induction of the epithelial-to-mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGF beta 1 cascade suppresses EMT and the resultant fibrosis. In this study, we focus on EMT-induced fibrosis in hepatocytes and the epigenetic regulation of the type I collagen gene. Histone acetylation is an important, major epigenetic mechanism that modulates gene transcription. We evaluated the epigenetic regulation of type I collagen in alpha mouse liver 12 hepatocytes (an tuaransformed mouse cell line) that had undergone EMT after treatment with TGF beta 1. The histone deacetylase inhibitor trichostatin A (TSA) inhibited EMT; this was reflected by the preservation of epithelial markers and function (E-cadherin and albumin). Fibrosis, the ultimate outcome of EMT, was abolished by TSA; this was indicated by the inhibition of type I collagen deposition. TSA exerted its anti-EMT effects by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription Complex and by interfering with p300, a coactivator of the type I collagen promoter, and preventing its binding to Smad3. TSA also restored Friend leukemia virus integration 1, an inhibitor of the type I collagen gene. TGF beta 1-induced EMT and its inhibition by TSA were replicated in human primary hepatocytes. Conclusion: Histone deacetylase inhibition abrogates TGF beta 1-induced EMT in hepatocytes and reverses EMT-induced fibrosis by epigenetic modulation of type I collagen. (HEPATOLOGY 2010;52:1033-1045)