SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury

Objectives: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury. Background: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined. Methods: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation. Results: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3 beta (GSK-3 beta) and beta-catenin, and promotes phosphorylation and degradation of beta-catenin, leading to suppression of the downstream FOXOs, and activation of NF-kappa Band TLR4 signaling. Furthermore, activation of beta-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage. Conclusions: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/beta-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries.