Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis
Articolo
Data di Pubblicazione:
2020
Citazione:
Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis / X. Wang, B. Cai, X. Yang, O.O. Sonubi, Z. Zheng, R. Ramakrishnan, H. Shi, L. Valenti, U.B. Pajvani, J. Sandhu, R.E. Infante, A. Radhakrishnan, D.F. Covey, K.L. Guan, J. Buck, L.R. Levin, P. Tontonoz, R.F. Schwabe, I. Tabas. - In: CELL METABOLISM. - ISSN 1550-4131. - 31:5(2020 May 05), pp. 969-986. [10.1016/j.cmet.2020.03.010]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
ADCY10; cholesterol; Gramd1/ASTER; Hippo; liver fibrosis; NASH; RhoA; sAC; TAZ; WWTR1
Elenco autori:
X. Wang, B. Cai, X. Yang, O.O. Sonubi, Z. Zheng, R. Ramakrishnan, H. Shi, L. Valenti, U.B. Pajvani, J. Sandhu, R.E. Infante, A. Radhakrishnan, D.F. Covey, K.L. Guan, J. Buck, L.R. Levin, P. Tontonoz, R.F. Schwabe, I. Tabas
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