基于MAPK途径探讨丹蛭降糖胶囊改善高脂血症大鼠肝损伤的机制

Mechanism of Danzhi Jiangtang Capsules on improving liver injury in hyperlipidemia rats based on MAPK pathway

探究丹蛭降糖胶囊对高脂血症大鼠肝脏损伤的保护作用及初步机制。采用高脂饲料喂养12周制备雄性SD大鼠高脂血症模型,模型成功后分为模型对照组、丹蛭降糖胶囊2个剂量组(500,1 000 mg·kg-1·d-1),连续灌胃给药8周。分析血脂和肝代谢指标,HE和油红O染色观察肝脏的病理学变化,RT-PCR法分析细胞外信号调节蛋白激酶1/2(ERK1/2)、c-Jun氨基末端激酶(JNK)及p38丝裂原活化蛋白激酶(p38 MAPK)的表达,免疫组化和Western blot法分析p-ERK,p-JNK,p-p38和MCP-1的表达。结果显示,丹蛭降糖胶囊能明显降低大鼠体质量和血清TC,TG,ALT,AST水平,升高HDL-C水平,逆转高脂饮食诱导的肝损伤及脂质沉积,降低ERK1/2,JNK,p-38 MAPK mRNA水平,降低p-ERK,p-JNK,p-p38,MCP-1蛋白表达水平,且具有一定的剂量效应。因此,丹蛭降糖胶囊可通过抑制MAPK途径和炎症而改善高脂血症大鼠的肝损伤,并有一定的剂量效应。

This study aimed to investigate the protective effect and preliminary mechanism of Danzhi Jiangtang Capsules(DJC)on liver of hyperlipidemic rats.The hyperlipidemia models were successfully made by high-fat diet for 12 weeks in male SD rats,and then divided into model control group and DJC treatment groups(500 and 1 000 mg·kg-1·d-1)via gavage administration for additional 8 weeks.The levels of serum lipid and liver metabolism indices were detected;HE and oil red O staining were used to observe the pathological changes of liver.Expression levels of extracellular regulated protein kinase 1/2(ERK1/2),c-Jun N-terminal kinase(JNK),and p38 mitogen-activated protein kinase(p38 MAPK)were detected by real-time polymerase chain reaction(RT-PCR).Expression of MCP-1,phosphorylated ERK(p-ERK),phosphorylated JNK(p-JNK),and phosphorylated p38 MAPK(p-p38)were analyzed by immunohistochemistry and Western blot.The results showed that DJC decreased body weight and serum levels of total cholesterol(TC),triglyceride(TG),alanine aminotransferase(ALT),aspartate aminotransferase(AST),increased serum high-density lipoprotein cholesterol(HDL-C)level,ameliorate injury and lipid deposition in the liver induced by the high-fat diet,decreased mRNA expression of ERK1/2,JNK and p-38 MAPK as well as protein expression of p-ERK,p-JNK,p-p38,and MCP-1,somewhat showing a dose-dependent effect.Therefore,DJC has an obvious protective effect on liver of hyperlipidemic rats with certain dose-dependent effect,and the mechanism may be related with inhibiting MAPK pathways and inflammation.