SIRT1激动剂通过作用于HMGB1调控急性肝衰竭中的铁死亡  

SIRT1 agonist regulates ferroptosis in acute liver failure by acting on HMGB1

作　　者：张艳琼 沈起艳 张龙[1] 张小雅 王鲁文 龚作炯[1] ZHANG Yanqiong;SHEN Qiyan;ZHANG Long;ZHANG Xiaoya;WANG Luwen;GONG Zuojiong(Department of Infectious Diseases,Renmin Hospital of Wuhan University,Hubei Province,Wuhan430060,China)

机构地区：[1]武汉大学人民医院感染科,湖北武汉430060

出　　处：《中国医药导报》2024年第30期36-40,共5页China Medical Herald

基　　金：湖北省自然科学基金资助项目(2022CFB120)。

摘　　要：目的探讨沉默信息调控因子2相关酶1(SIRT1)和高迁移率族蛋白1(HMGB1)在急性肝衰竭(ALF)中的作用。方法脂多糖联合D-氨基半乳糖(LPS/D-Gal)在体外诱导小鼠肝细胞(AML-12细胞)急性肝损伤模型,进一步运用SIRT1激动剂CAY10602和HMGB1抑制剂甘草酸(GLY)进行干预,将细胞分为五组:正常组、LPS/D-Gal组、LPS/D-Gal+CAY10602组、LPS/D-Gal+GLY组和LPS/D-Gal+CAY10602+GLY组,并观察SIRT1与HMGB1的相互作用。检测铁死亡相关蛋白谷胱甘肽过氧化物酶4(GPX4)和酰基辅酶A合成酶长链家族成员4(ACSL4)的表达,观察SIRT1和HMGB1对铁死亡的影响。结果与正常组比较,LPS/D-Gal组胞质中HMGB1荧光强度增加,SIKT1荧光强度降低。与正常组比较,LPS/D-Gal组HMBG1蛋白表达水平升高,SIRT1蛋白表达水平降低(P<0.05)。与LPS/D-Gal组比较,LPS/D-Gal+CAY10602组和LPS/D-Gal+GLY组HMGB1蛋白水平降低(P<0.05)。与LPS/D-Gal+GLY组比较,LPS/D-Gal+CAY10602+GLY组HMBG1蛋白表达水平降低(P<0.05)。与LPS/D-Gal组比较,LPS/D-Gal+CAY10602组SIRT1蛋白表达水平升高(P<0.05)。共聚焦结果显示SIRT1和HMGB1在细胞中共定位,免疫沉淀结果显示SIRT1与HMGB1有相互结合。与LPS/D-Gal组比较,LPS/D-Gal+CAY10602组和LPS/D-Gal+GLY组铁死亡相关蛋白GPX4的表达升高,ACSL4的表达降低(P<0.05)。结论SIRT1可以通过调节HMGB1促进GPX4的表达,抑制ACSL4的表达,从而减轻ALF中的铁死亡。Objective To explore the role of silencing information regulator 2 related enzyme 1(SIRT1)and high mobility group box 1(HMGB1)in acute liver failure(ALF).Methods Lipopolysaccharide/D-galactosamine(LPS1 D-Gal)were used to induce ALF model in vitro.SIRT1 agonist CAY10602 and HMGB1 inhibitor glycyrrhizin(GLY)were used to intervene.The cells were divided into five groups:normal group,LPS/D-Gal group,LPS/D-Gal+CAY10602 group,LPS/D-Gal+GLY group,and LPS/D-Gal+CAY10602+GLY group.The interaction between SIRT1 and HMGB1 was observed.The expressions of ferroptosis-related proteins glutathione peroxidase 4(GPX4)and acyl-CoA synthetase long-chain family member 4(ACSL4)were also detected to observe the effects of SIRT1 and HMGB1 on ferroptosis.Results Compared with the normal group,the fluorescence intensity of HMGB1 in the cytoplasm of LPS/D-Gal group was increased and the fluorescence intensity of SIRT1 decreased.Compared with normal group,HMBG1 protein expression level was increased and SIRT1 protein expression level was decreased in LPS/D-Gal group(P<0.05).The protein level of HMGB1 was decreased in LPS/D-Gal+CAY10602 group and LPS/D-Gal+GLY group compared with LPS/D-Gal group.Compared with LPS/D-Gal+GLY group,HMBG1 protein expression level in LPS/D-Gal+CAY10602+GLY group was decreased(P<0.05).Compared with LPS/D-Gal group,SIRT1 protein expression level in LPS/D-Gal+CAY10602 group was increased(P<0.05).Confocal immunofluorescence results showed that SIRT1 and HMGB1 co-located in cells and immunoprecipitation results showed that HMGB1 combined with SIRT1 in cells.Compared with LPS/D-Gal group,the expression of ferroptosis-related protein protein GPX4 in LPS/D-Gal+CAY10602 and LPS/D-Gal+GLY groups was increased,and the expression of ACSL4 was decreased(P<0.05).Conclusion SIRT1 can promote the expression of GPX4 and inhibit the expression of ACSL4 by regulating HMGB1,thus reducing ferroptosis.

关 键 词：急性肝衰竭 沉默信息调控因子2相关酶1 高迁移率族蛋白1 铁死亡 

分 类 号：R575.3[医药卫生—消化系统]