An RORα agonist, ODH-08, inhibits fibrogenic activation of hepatic stellate cells via suppression of SMAD3
- Authors
- Choi, Haena; Oh, Daehyun; Kim, Hyeon-Ji; Chambugong, Melody; Kim, Mi-Hyun; Lee, Mi-Ock; Park, Hyeung-Geun
- Issue Date
- Mar-2024
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- ROR alpha; ODH-08; Hepatic stellate cells; Fibrosis; SMAD2/3
- Citation
- LIFE SCIENCES, v.340
- Journal Title
- LIFE SCIENCES
- Volume
- 340
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/91080
- DOI
- 10.1016/j.lfs.2024.122443
- ISSN
- 0024-3205
1879-0631
- Abstract
- Aims: Hepatic fibrosis is a dynamic process characterized by the net accumulation of an extracellular matrix resulting from chronic liver injury such as nonalcoholic steatohepatitis. Activation of hepatic stellate cells (HSCs) plays a role in transdifferentiation of quiescent cells into fibrogenic myofibroblasts. We aimed to examine the function of retinoic acid receptor -related orphan receptor alpha (ROR alpha) and its novel agonistic ligand, 1-(4benzyloxybenzyl)-3-(2-dimethylaminoethyl)-thiourea (ODH-08) against activation of HSCs using hepatic fibrosis mouse models. Main methods: Chemical synthesis, a reporter gene assay, surface plasmon resonance analysis, and a docking study were performed to evaluate ODH-08 as a ligand of ROR alpha. In vivo experiments with mice fed a Western diet were performed to evaluate the effect of ODH-08. The human HSC line, Lx -2, and primary mouse HSCs were employed to identify the molecular mechanisms underlying the antifibrogenic effect of ODH-08. Key findings: A novel ROR alpha-selective ligand, ODH-08, was developed based on modification of JC1-40, an analog of N-methylthiourea. Administration of ODH-08 to the Western diet -fed mice reduced hepatic collagen deposition and expression levels of fibrogenic markers such as alpha-smooth muscle actin and collagen type I alpha 1 chain. Activation of ROR alpha-either by transient overexpression of ROR alpha or treatment with ODH-08-suppressed the expression of fibrogenic proteins in HSCs. The activation of ROR alpha suppressed the activity of SMAD2 and 3, which are the primary downstream proteins of transforming growth factor beta. Significance: ROR alpha and its agonist ODH-08 have a potent antifibrotic effect, which could provide a novel antifibrotic strategy against hepatic fibrosis.
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