title: RAR-Related Orphan Receptor Gamma (ROR-γ) Mediates Epithelial-Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis.
abstract: The epithelial-mesenchymal transition (EMT) is involved in many different types of cellular behavior, including liver fibrosis. In this report, we studied a novel function of RAR-related orphan receptor gamma (ROR-γ) in hepatocyte EMT during liver fibrosis. To induce EMT in vitro, primary hepatocytes and FL83B cells were treated with TGF-β1. Expression of ROR-γ was analyzed by Western blot in the fibrotic mouse livers and human livers with cirrhosis. To verify the role of ROR-γ in hepatocyte EMT, we silenced ROR-γ in FL83B cells using a lentiviral short hairpin RNA (shRNA) vector. The therapeutic effect of ROR-γ silencing was investigated in a mouse model of TAA-induced fibrosis by hydrodynamic injection of plasmids. ROR-γ expression was elevated in hepatocyte cells treated with TGF-β1, and ROR-γ protein levels were elevated in the fibrotic mouse livers and human livers with cirrhosis. Knockdown of ROR-γ resulted in the attenuation of TGF-β1-induced EMT in hepatocytes. Strikingly, ROR-γ bound to ROR-specific DNA response elements (ROREs) in the promoter region of TGF-β type I receptor (Tgfbr1) and Smad2, resulting in the downregulation of Tgfbr1 and Smad2 after silencing of ROR-γ. Therapeutic delivery of shRNA against ROR-γ attenuated hepatocyte EMT and ameliorated liver fibrosis in a mouse model of TAA-induced liver fibrosis. Overall, our results suggest that ROR-γ regulates TGF-β-induced EMT in hepatocytes during liver fibrosis. We suggest that ROR-γ may become a potential therapeutic target in treating liver fibrosis. J. Cell. Biochem. 118: 2026-2036, 2017. © 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Sung Min
authors: SM
authors: Kim
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Jung Eun
authors: JE
authors: Choi
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Wonhee
authors: W
authors: Hur
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Jung-Hee
authors: JH
authors: Kim
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Sung Woo
authors: SW
authors: Hong
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Eun Byul
authors: EB
authors: Lee
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.
authors: Joon Ho
authors: JH
authors: Lee
authors: Molecular Medicine Research Center, School of Medical Science, Chifeng University, Chifeng, 024000, China.
authors: Tian Zhu
authors: TZ
authors: Li
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.|Department of Internal Medicine, Seoul St. Mary's Hospital, #505 Banpo-Dong, Seocho-gu, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
authors: Pil Soo
authors: PS
authors: Sung
authors: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, Seocho-gu, Seoul, 06591, Republic of Korea.|Department of Internal Medicine, Seoul St. Mary's Hospital, #505 Banpo-Dong, Seocho-gu, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
authors: Seung Kew
authors: SK
authors: Yoon
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013853:Thioacetamide; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D013853:Thioacetamide; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: EPITHELIAL-MESENCHYMAL TRANSITION; LIVER FIBROSIS; ROR-γ; TRANSFORMING GROWTH FACTOR-β1