Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology

Background & aims Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. Methods Hepatocyte-specific SRY knock-in (KI), SRY knockout (KO), and SRY KI with platelet-derived growth factor receptor α (PDGFRα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation (BDL) for 2 weeks or carbon tetrachloride (CCl4) treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. Results Similarly, male mice developed more severe toxin- or cholestasis-induced liver fibrosis than females in surgically castrated mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. SRY KI mice developed exacerbated liver fibrosis, whereas SRY KO mice had alleviated liver fibrosis after BDL or administration of CCl4 than the age- and sex-matched control mice. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate PDGFRα expression, and promote high mobility group box 1 (HMGB1) release and subsequent HSCs activation. Knockout of PDGFRα or treatment with the SRY inhibitor DAX1 in SRY KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. Conclusions SRY is a strong pro-fibrotic factor and accounts for the sex disparity of liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease.