RAR-Related Orphan Receptor Gamma (ROR-γ) Mediates Epithelial-Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis.

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-) in hepatocyte EMT during liver fibrosis. To induce EMT in vitro, primary hepatocytes and FL83B cells were treated with TGF-1. Expression of ROR- was analyzed by Western blot in the fibrotic mouse livers and human livers with cirrhosis. To verify the role of ROR- in hepatocyte EMT, we silenced ROR- in FL83B cells using a lentiviral short hairpin RNA (shRNA) vector. The therapeutic effect of ROR- silencing was investigated in a mouse model of TAA-induced fibrosis by hydrodynamic injection of plasmids. ROR- expression was elevated in hepatocyte cells treated with TGF-1, and ROR- protein levels were elevated in the fibrotic mouse livers and human livers with cirrhosis. Knockdown of ROR- resulted in the attenuation of TGF-1-induced EMT in hepatocytes. Strikingly, ROR- bound to ROR-specific DNA response elements (ROREs) in the promoter region of TGF- type I receptor (Tgfbr1) and Smad2, resulting in the downregulation of Tgfbr1 and Smad2 after silencing of ROR-. Therapeutic delivery of shRNA against ROR- attenuated hepatocyte EMT and ameliorated liver fibrosis in a mouse model of TAA-induced liver fibrosis. Overall, our results suggest that ROR- regulates TGF--induced EMT in hepatocytes during liver fibrosis. We suggest that ROR- may become a potential therapeutic target in treating liver fibrosis. J. Cell. Biochem. 118: 2026-2036, 2017. (c) 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.