Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis
Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis
复制标题
Ets-1缺陷通过削弱TGF-β1信号介导的肝细胞凋亡来减轻非酒精性脂肪性肝炎
DOI：
10.1038/s41419-019-1672-4
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发表时间：
2019-06-12
影响因子：
9
通讯作者：
Han, Xiao
中科院分区：
文献类型：
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作者：
Liu, Dechen;Wang, Kai;Han, Xiao
肝细胞凋亡是非酒精性脂肪性肝炎（NASH）的标志，并导致肝损伤、纤维化和炎症。然而，NASH中肝细胞过度凋亡的分子机制仍不清楚。本研究旨在探讨禽成红细胞增多症病毒E26癌基因同源物1（Ets-1）是否以及如何参与饮食诱导的小鼠肝细胞凋亡。该研究发现，在NASH小鼠模型中，由于转化生长因子β 1（TGF-β 1）信号转导的激活，肝脏Ets-1的表达水平升高。在TGF-β 1的存在下，针对十肢瘫痪同源物2/3（pSmad 2/3）的磷酸化母体易位到Ets-1启动子的结合位点，以上调原代肝细胞中Ets-1的表达。此外，Ets-1直接与磷酸化Smad 3（p-Smad 3）结合，从而阻止p-Smad 3的泛素化和蛋白酶体降解，并增强TGF-β 1/Smad 3信号传导的活性。因此，升高的Ets-1刺激TGF-β 1诱导的肝细胞凋亡。然而，Ets-1敲低减轻了饮食诱导的肝细胞凋亡和NASH，减少了肝损伤、炎症和纤维化。总之，Ets-1对TGF-β 1治疗下的肝细胞存活有不利影响，并加速小鼠NASH的发展。
Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-beta 1) signaling. In the presence of TGF-beta 1, phosphorylated mothers against decapentaplegic homolog 2/3 (pSmad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-beta 1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-beta 1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-beta 1 treatment and accelerated the development of NASH in mice.