Title | Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K-L, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I |
Journal | Cell Metab |
Volume | 31 |
Issue | 5 |
Pagination | 969-986.e7 |
Date Published | 2020 May 05 |
ISSN | 1932-7420 |
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. |
DOI | 10.1016/j.cmet.2020.03.010 |
Alternate Journal | Cell Metab |
PubMed ID | 32259482 |
PubMed Central ID | PMC7313619 |
Grant List | P01 HL020948 / HL / NHLBI NIH HHS / United States R01 HD088571 / HD / NICHD NIH HHS / United States R35 CA196878 / CA / NCI NIH HHS / United States R01 DK103818 / DK / NIDDK NIH HHS / United States T32 HL007343 / HL / NHLBI NIH HHS / United States R01 DK116620 / DK / NIDDK NIH HHS / United States P01 HL087123 / HL / NHLBI NIH HHS / United States R01 MH110550 / MH / NIMH NIH HHS / United States R01 DE015964 / DE / NIDCR NIH HHS / United States R01 AG061290 / AG / NIA NIH HHS / United States R01 HL132412 / HL / NHLBI NIH HHS / United States R01 HL136618 / HL / NHLBI NIH HHS / United States HHSN276201200017C / LM / NLM NIH HHS / United States P30 CA013696 / CA / NCI NIH HHS / United States R01 DK119767 / DK / NIDDK NIH HHS / United States K99 DK115778 / DK / NIDDK NIH HHS / United States R01 HL067773 / HL / NHLBI NIH HHS / United States |