SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury
SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury
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SRY 是肝缺血/再灌注损伤中性别二态性的关键调节因子
DOI：
10.1097/sla.0000000000004422
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发表时间：
2022-08-01
影响因子：
9
通讯作者：
Zhang, Xu-Feng
中科院分区：
文献类型：
--
作者：
Dong, Jian;Ke, Meng-Yun;Zhang, Xu-Feng
目的：确定男性特有基因 SRY 在缺血再灌注引起的肝损伤中的作用和机制。背景：男性比女性更容易受到缺血再灌注损伤。然而，这些基于性别的差异的机制仍不清楚。方法：从国际多机构数据库中确定接受肝切除术的患者的临床病理数据。生成肝脏特异性 SRY TG 小鼠，并与其同窝 WT 对照小鼠一起在体内经受 I/R 损伤。通过缺氧/复氧刺激处理 TG 和 WT 小鼠的原代肝细胞进行体外实验。结果：临床数据显示，1267 名接受肝切除术的男性患者术后转氨酶水平、总体发病率和肝衰竭发生率明显高于 508 名女性患者。 SRY 在肝 I/R 损伤期间显着上调。与WT相比，雄性TG小鼠中SRY的过度表达和雌性TG小鼠中SRY的异位表达加剧了肝I/R损伤，表现为体内和体外炎症反应、氧化应激和细胞死亡增加。从机制上讲，SRY 与糖原合成酶激酶 3 beta (GSK-3 beta) 和 β-catenin 相互作用，促进 β-catenin 磷酸化和降解，从而抑制下游 FOXO，并激活 NF-kappa Band TLR4 信号传导。此外，β-catenin的激活几乎完全逆转了SRY过表达介导的肝I/R损伤加剧。结论：SRY是一种新型的肝I/R介质，通过抑制Wnt/β-catenin信号传导促进肝脏炎症反应、氧化应激和细胞坏死，这解释了肝I/R损伤中性别差异的原因。
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.