HDAC2抑制剂CAY10683通过自噬对急性肝衰竭小鼠的保护作用

HDAC2 inhibitor CAY10683 demonstrates protective effects in mice with acute liver failure through autophagy enhancement

目的:探究HDAC2抑制剂CAY10683在急性肝衰竭小鼠模型中的保护机制。方法:将C57BL/6雄性小鼠随机分为正常组、模型组、CAY10683组、自噬抑制剂MRT68921组和CAY10683/MRT68921联合组。D-氨基半乳糖和脂多糖诱导建立急性肝衰竭小鼠模型,获取小鼠血清及肝脏标本。检测血清中丙氨酸氨基转移酶和天门冬氨酸氨基转移酶含量;一部分肝组织用于HE染色和电镜下观察,另一部分肝组织用于生化检测,蛋白质印迹法检测自噬蛋白UNC-51样激酶1和苹果酸脱氢酶1(MDH1)的相对含量,生化试剂盒检测组织中葡萄糖、丙酮酸、乳酸和乳酸脱氢酶含量。结果:CAY10683可增加急性肝衰竭小鼠模型中肝脏内的自噬水平,对小鼠肝脏具有一定的保护作用,CAY10683可降低急性肝衰竭小鼠模型中肝组织内的葡萄糖、丙酮酸、乳酸和LDH含量,增加肝组织内MDH1含量;MRT68921则相反;CAY10683一定程度上可拮抗MRT68921的作用。结论:HDAC2抑制剂CAY10683在小鼠肝衰竭进程中可能通过提高自噬水平改善肝脏内代谢,对肝脏起到一定的保护作用。

Objective:To explore the protective mechanism of HDAC2 inhibitor CAY10683 in an acute liver failure mouse model.Methods:C57BL/6 male mice were randomly divided into normal group,model group,CAY10683 group,autophagy inhibitor MRT68921 group and CAY10683/MRT68921 combined group.A mouse model of acute liver failure was induced by D-galactosamine and lipopolysaccharide.Serum and liver samples were obtained.The serum levels of alanine aminotransferase and aspartate aminotransferase were detected.One part of the liver tissue was used for HE staining and electron microscopy,and the other part was used for biochemical detection.Western blotting was used to detect the relative contents of autophagy protein UNC-51-like kinase 1 and malate dehydrogenase 1(MDH1).Results:The CAY10683 increased the level of autophagy in the acute liver failure mouse model and had a protective effect on the mouse liver.The CAY10683 decreased the glucose,pyruvate,lactate,and LDH contents in liver tissues and increased the MDH1 content in liver tissues in acute liver failure mouse model.The MRT68921 increased the glucose,pyruvate,lactate,and LDH contents in liver tissues and decreased the MDH1 content in liver tissues in acute liver failure mouse model.The CAY10682 antagonized the effect of MRT68921.Conclusion:The HDAC2 inhibitor CAY10683 may improve glucose metabolism by increasing autophagy levels in the process of liver failure in mice and has a protective effect on the liver.