美国哥伦比亚大学欧文医学中心Ira Tabas和Xiaobo Wang小组近日取得一项新成果。他们发现胆固醇通过稳定肝细胞中的转录因子TAZ促进非酒精性脂肪性肝炎（NASH）。2020年4月6日，该成果在线发表在《细胞-代谢》杂志上。

研究人员发现肝细胞中胆固醇增加会上调TAZ并促进纤维化NASH。ASTER-B / C介导的质膜胆固醇内在化激活了可溶性腺苷酸环化酶（sAC; ADCY10），引起钙-RhoA介导的途径，抑制β-TrCP/蛋白酶体介导的TAZ降解。

给小鼠饲喂富含胆固醇的NASH诱导饮食，肝细胞特异性的ASTER-B / C、sAC或RhoA沉默可降低TAZ并改善纤维化NASH。胆固醇-TAZ途径存在于人原代肝细胞中，并且与人NASH肝脏中的胆固醇、TAZ和RhoA途径相关联。因此，肝细胞胆固醇通过增加TAZ表达促进纤维化NASH，这为NASH治疗干预提供了新的靶点。

据悉，尚不完全了解肝脂肪变性如何转变为纤维化NASH的，其治疗选择有限。在人类NASH肝脏的肝细胞中，胆固醇（其与NASH的机理联系尚不完全清楚）和TAZ（可促进纤维化，但其NASH升高的机制尚不清楚）是表达显著升高的两个分子。

附：英文原文

Title: Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis

Author: Xiaobo Wang, Bishuang Cai, Xiaoming Yang, Oluwatoni O. Sonubi, Ze Zheng, Rajasekhar Ramakrishnan, Hongxue Shi, Luca Valenti, Utpal B. Pajvani, Jaspreet Sandhu, Rodney E. Infante, Arun Radhakrishnan, Douglas F. Covey, Kun-Liang Guan, Jochen Buck, Lonny R. Levin, Peter Tontonoz, Robert F. Schwabe, Ira Tabas

Issue&Volume: 2020-04-06

Abstract: Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholicsteatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevatedin hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASHremains incompletely understood, and TAZ, a transcriptional regulator that promotesfibrosis but whose mechanism of increase in NASH is unknown. We now show that increasedhepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediatedinternalization of plasma membrane cholesterol activates soluble adenylyl cyclase(sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediatedTAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specificsilencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH.The cholesterol-TAZ pathway is present in primary human hepatocytes, and associationsamong liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with thepathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ,suggesting new targets for therapeutic intervention.

DOI: 10.1016/j.cmet.2020.03.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30125-X