组蛋白去乙酰化酶抑制剂ACY1215通过调控能量代谢酶保护脂多糖/D-氨基半乳糖诱导的急性肝衰竭小鼠机制研究  

Mechanism of histone deacetylase inhibitor ACY1215 in inhibition of LPS/D-galactosamine-induced acute liver failure in mice

作　　者：张小雅 石春霞 郭金 王钰鲲 张丹眉 沈起艳 龚作炯[1] Zhang Xiaoya;Shi Chunxia;Guo Jin(Department of Infectious Diseases,People’s Hospital,Affiliated to Wuhan University,Wuhan 430060,Hubei Province,China)

机构地区：[1]武汉大学人民医院感染病科,武汉市430060

出　　处：《实用肝脏病杂志》2024年第6期812-815,共4页Journal of Practical Hepatology

基　　金：国家自然科学基金资助项目(编号:82270627)。

摘　　要：目的探讨组蛋白去乙酰化酶(HDAC)抑制剂ACY1215对急性肝衰竭(ALF)小鼠的保护作用及其可能的作用机制。方法将30只小鼠随机分为对照组、模型组和ACY1215处理组,采用脂多糖和D-氨基半乳糖联合腹腔注射诱导小鼠ALF模型,常规行血生化和组织病理学检查,采用Western blot法检测肝组织苹果酸脱氢酶1(MDH1)、异柠檬酸脱氢酶(IDH1)和果糖-2,6-二磷酸酶2(PFKFB2)及白介素-1β(IL-1β)和IL-18分子蛋白的表达。结果肝组织病理学检查显示,ALF模型制备成功,而ACY1215干预组肝组织病理学损害显著减轻;模型组血清ALT、AST和TBIL水平分别为(3743.5±655.9)U/L、(2539.4±488.1)U/L和(89.56±7.2)μmol/L,显著高于对照组【分别为(34.5±7.6)U/L、(32.3±9.3)U/L和(6.2±2.4)μmol/L,P<0.05】,而ACY1215处理组各项指标均显著降低【分别为(951.5±328.9)U/L、(475.3±131.24)U/L和(38.41±9.5)μmol/L,P<0.05】;模型组小鼠肝组织MDH1和IDH1表达较对照组显著减弱,PFKFB2、IL-18和IL-1β表达较对照组显著增强,而ACY1215干预组肝组织MDH1和IDH1表达较模型组显著增强,而PFKFB2、IL-18和IL-1β表达较模型组显著减弱。结论组蛋白去乙酰化酶抑制剂ACY1215可以通过对能量代谢酶的调节发挥保护ALF小鼠的作用。Objective This experiment was conducted to explore the mechanism of protective roles of histone deacetylase(HDAC)inhibitor ACY1215 in inhibition of acute liver failure(ALF).Methods Thirty mice were randomly divided into control,model and ACY1215-intervened groups,with 10 animals in each.ALF model was established by combination of lipopolysaccharide and D-aminogalactose intraperitoneal injection,and early intraperitoneal ACY1215 injection was carried out as intervention.Histopathological examination was performed.Hepatic expression of malate dehydrogenase 1(MDH1),isocitrate dehydrogenase(IDH1),and fructose-2,6-bisphosphatase 2(PFKFB2)as well as interleukin-1β(IL-1β)and IL-18 were detected by Western blot.Results Histopathological examination demonstrated the ALF model was successfully established,and ACY1215 intervention greatly ameliorate liver injuries;serum ALT,AST and total bilirubin levels in the model group were(3743.5±655.9)U/L,(2539.4±488.1)U/L and(89.56±7.2)μmol/L,significantly higher than[(34.5±7.6)U/L,(32.3±9.3)U/L and(6.2±2.4)μmol/L,respectively,P<0.05]in the control,while ACY1215 intervention greatly decreased those parameters,e.g.,(951.5±328.9)U/L,(475.3±131.24)U/L and(38.41±9.5)μmol/L(P<0.05);hepatic expression of MDH1 and IDH1 in the model was obviously weaker,that of PFKFB2,IL-18 and IL-1βwas greatly intensified as compared to in the control,while in ACY1215-intervende group,the expression of MDH1 and IDH1 intensified,and PFKFB2,IL-18 and IL-1βweakened compared to in the model group.Conclusion The histone deacetylase inhibitor,ACY1215,could have a protective effects on mice with ALF,the mechanism by which it exert might be related to regulation of energy metabolism enzymes.

关 键 词：急性肝衰竭 组蛋白去乙酰化酶抑制剂 脂多糖和D-氨基半乳糖 苹果酸脱氢酶1 异柠檬酸脱氢酶1 果糖-2 6-二磷酸酶2 小鼠 

分 类 号：R575.3[医药卫生—消化系统]