@article{bac9349e2abb4d23a3d3e291996e43ac,
title = "Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis",
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.",
keywords = "ADCY10, Gramd1/ASTER, Hippo, NASH, RhoA, TAZ, WWTR1, cholesterol, liver fibrosis, sAC",
author = "Xiaobo Wang and Bishuang Cai and Xiaoming Yang and Sonubi, {Oluwatoni O.} and Ze Zheng and Rajasekhar Ramakrishnan and Hongxue Shi and Luca Valenti and Pajvani, {Utpal B.} and Jaspreet Sandhu and Infante, {Rodney E.} and Arun Radhakrishnan and Covey, {Douglas F.} and Guan, {Kun Liang} and Jochen Buck and Levin, {Lonny R.} and Peter Tontonoz and Schwabe, {Robert F.} and Ira Tabas",
note = "Funding Information: We thank Mengmeng Zhu and Guoan Zhang from the Proteomics and Metabolomics Core Facility at Weill Cornell Medicine for conducting the mass spectrometry analysis of TAZ S117 phosphorylation; Drs. Marion Namenwirth and Abigail Knoble (University of Minnesota) and Nicole Martik (University of Pittsburgh) for arranging and providing human liver samples and primary hepatocytes, respectively; and Dr. Jay Horton (University of Texas Southwestern) for providing hSREBP-2(1–468) plasmid. Human liver samples and primary hepatocytes were obtained from the Liver Tissue Cell Distribution System (University of Minnesota and University of Pittsburgh), which was funded by NIH contract HHSN276201200017C. Samples for histological analysis were prepared in the Molecular Pathology Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH/ NCI grant # P30 CA013696 . This work was supported by an American Liver Foundation Liver Scholar Award (to X.W.); NIH grant 1K99DK115778 (to B.C.); CAS “Light of West China” Program XAB2018AW09 (to X.Y); NIH- NHLBI Postdoctoral Fellow institutional training grant T32HL007343 , a fellow scholar award from the American Society of Hematology, and a career development award 19CDA34660043 from the American Heart Association (to Z.Z.); MyFirst grant Associazione Italiana per la Ricerca Sul Cancro (AIRC) n. 16888 “EPIDEMIC-NAFLD” (to L.V.); Ricerca Finalizzata Ministero della Salute RF-2016-02364358 (to L.V.); Ricerca Corrente Fondazione IRCCS Ca{\textquoteright} Granda Ospedale Maggiore Policlinico , (to L.V.); the European Union (EU) Programme Horizon 2020 (under grant agreement no. 777377) for the project LITMUS-“Liver Investigation: Testing Marker Utility in Steatohepatitis” (to L.V.); NIH grant HL20948 (to A.R. and R.E.I.); Welch Foundation grant I-1793 (to A.R.); NIH grants HD088571 and AG061290 (to J.B. and L.R.L.); the Taylor Family Institute for Innovative Psychiatric Research and NIH grant HL067773 (to D.F.C.); NIH grants DK103818 and DK119767 (to U.B.P.); NIH grants R35CA196878 and DE015964 (to K.-L.G.); NIH grant HL136618 (to P.T.); and NIH grants DK116620 , HL132412 , and HL087123 (to I.T.). Funding Information: We thank Mengmeng Zhu and Guoan Zhang from the Proteomics and Metabolomics Core Facility at Weill Cornell Medicine for conducting the mass spectrometry analysis of TAZ S117 phosphorylation; Drs. Marion Namenwirth and Abigail Knoble (University of Minnesota) and Nicole Martik (University of Pittsburgh) for arranging and providing human liver samples and primary hepatocytes, respectively; and Dr. Jay Horton (University of Texas Southwestern) for providing hSREBP-2(1?468) plasmid. Human liver samples and primary hepatocytes were obtained from the Liver Tissue Cell Distribution System (University of Minnesota and University of Pittsburgh), which was funded by NIH contract HHSN276201200017C. Samples for histological analysis were prepared in the Molecular Pathology Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH/NCI grant #P30 CA013696. This work was supported by an American Liver Foundation Liver Scholar Award (to X.W.); NIH grant 1K99DK115778 (to B.C.); CAS ?Light of West China? Program XAB2018AW09 (to X.Y); NIH-NHLBI Postdoctoral Fellow institutional training grant T32HL007343, a fellow scholar award from the American Society of Hematology, and a career development award 19CDA34660043 from the American Heart Association (to Z.Z.); MyFirst grant Associazione Italiana per la Ricerca Sul Cancro (AIRC) n.16888 ?EPIDEMIC-NAFLD? (to L.V.); Ricerca Finalizzata Ministero della Salute RF-2016-02364358 (to L.V.); Ricerca Corrente Fondazione IRCCS Ca? Granda Ospedale Maggiore Policlinico, (to L.V.); the European Union (EU) Programme Horizon 2020 (under grant agreement no. 777377) for the project LITMUS-?Liver Investigation: Testing Marker Utility in Steatohepatitis? (to L.V.); NIH grant HL20948 (to A.R. and R.E.I.); Welch Foundation grant I-1793 (to A.R.); NIH grants HD088571 and AG061290 (to J.B. and L.R.L.); the Taylor Family Institute for Innovative Psychiatric Research and NIH grant HL067773 (to D.F.C.); NIH grants DK103818 and DK119767 (to U.B.P.); NIH grants R35CA196878 and DE015964 (to K.-L.G.); NIH grant HL136618 (to P.T.); and NIH grants DK116620, HL132412, and HL087123 (to I.T.). X.W. and I.T. developed the study concept and experimental design; X.W. and O.O.S. conducted the mouse studies; X.W. X.Y. B.C. and H.S. performed the in vitro experiments and histological analyses; Z.Z. L.R.V. and U.B.P. took part in the studies with human liver specimens. D.F.C. A.R. P.T. K.-L.G. L.R.L. and J.B. provided critical reagents and advice; X.W. B.C. U.B.P. and I.T. analyzed the data; R.R. provided statistical support; and X.W. and I.T. wrote the manuscript. All authors read and commented on the manuscript. J.B. and L.R.L. own equity interest in CEP Biotech, which has licensed commercialization of a panel of monoclonal antibodies directed against sAC. I.T. and X.W. are co-inventors of a patent application related to the topic of this study, and I.T. is a scientific consultant for Genevant, which is developing therapies for NASH. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = may,
day = "5",
doi = "10.1016/j.cmet.2020.03.010",
language = "English",
volume = "31",
pages = "969--986.e7",
journal = "Cell metabolism",
issn = "1550-4131",
number = "5",
}