脂肪肝
内科学
脂肪变性
内分泌学
胰岛素抵抗
肝损伤
医学
脂滴
炎症
肝星状细胞
生物
非酒精性脂肪肝
自噬
脂质代谢
作者
Xiaobo Wang,Bishuang Cai,Xiaoming Yang,Oluwatoni O. Sonubi,Ze Zheng,Rajasekhar Ramakrishnan,Hongxue Shi,Luca Valenti,Utpal B. Pajvani,Jaspreet S. Sandhu,Rodney E. Infante,Arun Radhakrishnan,Douglas F. Covey,Kun-Liang Guan,Jochen Buck,Lonny R. Levin,Peter Tontonoz,Robert F. Schwabe,Ira Tabas
标识
DOI:10.1016/j.cmet.2020.03.010
摘要
Summary Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.
科研通智能强力驱动
Strongly Powered by AbleSci AI