Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Nonalcoholic Steatohepatitis

• Published in: Cell metabolism 2020-04, Vol.31 (5), p.969-986.e7
• Main Authors: Wang, Xiaobo, Cai, Bishuang, Yang, Xiaoming, Sonubi, Oluwatoni O., Zheng, Ze, Ramakrishnan, Rajasekhar, Shi, Hongxue, Valenti, Luca, Pajvani, Utpal B., Sandhu, Jaspreet, Infante, Rodney E., Radhakrishnan, Arun, Covey, Douglas F., Guan, Kun-Liang, Buck, Jochen, Levin, Lonny R., Tontonoz, Peter, Schwabe, Robert F., Tabas, Ira
• Format: Article
• Language: English
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.03.010

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 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. Cholesterol is consistently elevated in human NASH but its mechanistic link to NASH progression remains incompletely understood. Wang et al. now define a cholesterol-TAZ connection in which increased hepatocyte cholesterol upregulates TAZ through an adenylyl cyclase-calcium-RhoA pathway and promotes fibrotic NASH.