Sab在性别差异性急性肝损伤小鼠中的作用机制研究  

Mechanism of Sab in sexual dimorphism of acute liver injury in mice

作　　者：蒋逍达[1] 黄旭[1] 张军[1] JIANG Xiaoda;HUANG Xu;ZHANG Jun(Department of Gastroenterology,Renmin Hospital of Wuhan University/Hubei Key Laboratory of Digestive System Diseases,Wuhan,Hubei 430060,China)

机构地区：[1]武汉大学人民医院消化内科/消化系统疾病湖北省重点实验室,武汉430060

出　　处：《重庆医学》2025年第3期567-572,共6页Chongqing Medical Journal

基　　金：湖北省自然科学基金资助项目(2022CFB112)。

摘　　要：目的研究SH3结构域结合蛋白(Sab)在性别差异性急性肝损伤小鼠中的作用机制。方法将雌性小鼠和雄性小鼠随机分为对照组、乙酰氨基酚(APAP)急性肝损伤组、Ad-Sab组、雌激素受体拮抗组和雌激素受体激活组。各组小鼠在完成对应处理后收集肝脏组织、血清,随即进行ALT、AST检测,苏木精-伊红(HE)染色和Western blot实验。结果APAP急性肝损伤组雄性小鼠肝脏细胞质和线粒体中磷酸化c-Jun氨基末端激酶(p-JNK)活性高于雌性小鼠,差异有统计学意义(P<0.05);雄性小鼠Sab表达水平低于雌性小鼠,差异有统计学意义(P<0.05)。Ad-Sab组中,注射Ad-Sab的雄性小鼠肝脏损伤程度大于注射Ad-lacZ的雄性小鼠,Sab表达水平、ALT水平高于后者,差异有统计学意义(P<0.05)。雌激素受体拮抗组雌性小鼠仅采用富维司琼处理时,Sab表达水平随富维司琼剂量增加而提高;采用Ad-Sab+富维司琼处理的雌性小鼠在给予APAP 200 mg/kg 4 h后,肝脏损伤程度大于Ad-lacZ+富维司琼处理的雌性小鼠,ALT水平高于后者,差异有统计学意义(P<0.05)。雌激素受体激活组雄性小鼠受丙基吡唑三醇(PPT)保护,肝脏组织损伤小于对照组雄性小鼠,ALT水平低于对照组雄性小鼠,差异有统计学意义(P<0.05)。结论Sab的表达水平决定了c-Jun氨基末端激酶(JNK)依赖急性药物性肝损伤的严重程度。雌性小鼠肝脏Sab蛋白水平表达更低,对肝损伤具有明显抵抗力。Objective To investigate the mechanism of SH3 domain binding protein(Sab)in sex-differential acute liver injury in mice.Methods Female and male mice were randomly divided into control group,acetaminophen(APAP)-induced acute liver injury group,Ad-Sab group,estrogen receptor antagonist group and estrogen receptor agonist group.After corresponding treatments,liver tissues and serum were collected for ALT/AST detection,hematoxylin-eosin(HE)staining and Western blot analysis.Results In the APAP-induced acute liver injury group,male mice showed significantly higher p-JNK activity in hepatic cytoplasm and mitochondria than female mice(P<0.05).Male mice had lower Sab expression levels than female mice(P<0.05).In the Ad-Sab group,male mice injected with Ad-Sab showed more severe hepatic injury,higher Sab expression and elevated ALT levels compared with Ad-lacZ injected male mice(P<0.05).In the estrogen receptor antagonist group,fulvestrant-treated females showed dose-dependent increases in Sab expression.Female mice treated with Ad-Sab plus fulvestrant showed more severe liver injury and higher ALT levels than those receiving Ad-lacZ plus fulvestrant after 4 h of 200 mg/kg APAP administration exhibited more severe liver injury and higher ALT levels than controls(P<0.05).PPT-protected males in the estrogen receptor agonist group showed reduced hepatic damage and lower ALT levels compared with control male mice(P<0.05).Conclusion Sab expression level determines the severity of JNK-dependent acute drug-induced liver injury.Female mice have lower hepatic Sab protein expression levels and exhibit significant resistance to liver injury.

关 键 词：肝损伤 对乙酰氨基酚 性别差异性 SH3结构域结合蛋白 

分 类 号：R345.8[医药卫生—基础医学]