跨膜蛋白88通过促进活化肝星状细胞的凋亡和逆转来减轻肝纤维化。

Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and reversion of activated hepatic stellate cells.

作者信息

Cai Shuang-Peng, Cheng Xiao-Yu, Chen Pei-Jie, Pan Xue-Yin, Xu Tao, Huang Cheng, Meng Xiao-Ming, Li Jun

机构信息

School of Pharmacy, Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (ILD-AMU), Anhui Medical University, Hefei 230032, China.

出版信息

Mol Immunol. 2016 Dec;80:58-67. doi: 10.1016/j.molimm.2016.11.002. Epub 2016 Nov 7.

DOI:10.1016/j.molimm.2016.11.002

PMID:27833039

Abstract

Transmembrane protein 88 (Tmem88) is a crucial inhibitor for Wnt/β-catenin pathway in the development of myocardial cells. Due to the important role of β-catenin in the activation and proliferation of hepatic stellate cells (HSCs), it is necessary to investigate the function of Tmem88 in HSCs. In this study, we found that Tmem88 expression was decreased in the human liver fibrotic tissues, primary HSCs from fibrotic mice and activated HSC-T6 cells. Functionally, Tmem88 could inhibit HSCs activation and proliferation by blocking Wnt/β-catenin pathway, and promoted the apoptosis of activated HSCs by initiating Bcl-2/Bax/Caspase3 pathway. Moreover, the level of DNA metyltransferase 3a (Dnmt3a) was upregulated in activated HSCs, and siRNA-mediated Dnmt3a silencing led to Tmem88 restoration. These results indicated that Tmem88 played an important role in HSCs activation, proliferation and apoptosis, and Tmem88 expression might be modulated by Dnmt3a.

摘要

跨膜蛋白88（Tmem88）是心肌细胞发育过程中Wnt/β-连环蛋白信号通路的关键抑制剂。由于β-连环蛋白在肝星状细胞（HSC）的激活和增殖中具有重要作用，因此有必要研究Tmem88在HSC中的功能。在本研究中，我们发现Tmem88在人肝纤维化组织、纤维化小鼠的原代HSC以及活化的HSC-T6细胞中的表达均降低。在功能上，Tmem88可通过阻断Wnt/β-连环蛋白信号通路抑制HSC的激活和增殖，并通过启动Bcl-2/Bax/Caspase3信号通路促进活化HSC的凋亡。此外，DNA甲基转移酶3a（Dnmt3a）在活化的HSC中表达上调，siRNA介导的Dnmt3a沉默导致Tmem88恢复表达。这些结果表明，Tmem88在HSC的激活、增殖和凋亡中发挥重要作用，且Tmem88的表达可能受Dnmt3a调控。