title: Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis.
abstract: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: xw2279@columbia.edu.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
authors.forename: Jorge Matias
authors.initials: JM
authors.lastname: Caviglia
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Corey
authors.affiliation: Teklad Diets, Envigo, Madison, WI, 53713, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Herfel
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Bishuang
authors.initials: B
authors.lastname: Cai
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Department of Pathology and Laboratory Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Ricard
authors.initials: R
authors.lastname: Masia
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: iat1@columbia.edu.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse