Abstract
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 theSuv39h1f/fmice to theLrat-Cre mice or thePostn-CreERT2mice. Liver fibrosis was induced by CCl4injection 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.
Funder
National Natural Science Foundation of China
Wuxi Taihu Lake Talent Plan for Leading Talents in Medical and Health Profession
Natural Science Foundation of Jiangsu Province
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