Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis

• Published in: Gut Vol. 73; no. 5; pp. 810 - 824
• Main Authors: Kong, Ming, Zhou, Junjing, Kang, Aoqi, Kuai, Yameng, Xu, Huihui, Li, Min, Miao, Xiulian, Guo, Yan, Fan, Zhiwen, Xu, Yong, Li, Zilong
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 04.01.2024; BMJ Publishing Group LTD
• Subjects: Animal models; Animals; Bile ducts; Carbon tetrachloride; Cell activation; Cell culture; Cirrhosis; Cross-breeding; Epigenetics; Extracellular matrix; Fibrosis; Heme oxygenase (decyclizing); hepatic fibrosis; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatology; Histone methyltransferase; Homeostasis; Humans; Injuries; Liver - metabolism; Liver cancer; Liver cirrhosis; Liver Cirrhosis - pathology; Liver diseases; Mice; Myofibroblasts; Pharmaceuticals; Proteins; Stellate cells; Transcriptomics; Vitamin A; China; hepatic fibrosis
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2023-329671

ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.DesignHSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.ResultsWe report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.ConclusionsOur data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.