脂必泰对非酒精性脂肪肝病大鼠肝组织ERK和TLR4表达的影响

Effects of Zhibitai on the Expressions of ERK and TLRs in Liver Tissues of NAFLD Rats

目的:观察脂必泰对非酒精性脂肪性肝病大鼠肝组织ERK和TLR4表达的调控作用。方法:采用10%果糖和高脂饲料诱导非酒精性脂肪性肝病大鼠模型,将模型大鼠随机分为模型对照组、脂必泰100 mg/kg、200 mg/kg组、二甲双胍200 mg/kg组、水飞蓟宾100 mg/kg组,另设正常对照组。连续给药9周后,观察各组大鼠空腹血糖(FBG)、餐后2小时血糖(2hBG)及血清胰岛素(Fins)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、总胆固醇(CHOL)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平,并计算肝脏指数和胰岛素抵抗指数(HOMA-IR);以RT-PCR和Western blot法检测肝组织Toll样受体4(TLR4)、P-ERK1/2 mRNA及蛋白的表达。结果:与空白对照组比较,模型组2hBG、Fins、HOMA-IR、ALT、AST、TG、CHOL、HDL-C、LDL-C含量、肝脏指数及病理评分均明显升高,HDL-C含量明显降低,TLR4、P-ERK1/2 mRNA和蛋白表达水平明显上调。与模型对照组比较,脂必泰100、200 mg/kg组2hBG、Fins、HOMA-IR、ALT、AST、TG、CHOL、LDL-C含量及肝脏指数、组织病理评分均明显降低,HDL-C含量和AST/ALT比值明显升高,TLR4、P-ERK1/2 mRNA和蛋白表达水平明显下调。结论:脂必泰可通过下调TLR4、P-ERK1/2基因和蛋白的表达,影响MAPK-ERK-TLRs通路而抑制炎症信号通路的转导,阻止炎症的发生、发展,改善血脂,同时拮抗胰岛素抵抗,改善肝脏空泡变性,减轻肝脏炎症反应而起到保护肝脏的作用。

Objective:To observe effects of Zhibitai on ERK and TLR4 expression in liver tissues of non-alcoholic fatty liver disease(NAFLD)rats.Methods:The rat model with nonalcoholic fatty liver disease was induced by 10%fructose and high-fat diet.The model rats were randomly divided into the model group,metformin group(200 mg/kg),silymarin group(100 mg/kg)and Zhibitai groups(200 mg/kg,100 mg/kg),normal rats were set as the control group.After 9 weeks of administration,the levels of fasting blood glucose(FBG),postprandial 2 hours blood glucose(2 hBG)and serum insulin(Fins),alanine amino transferase(ALT),aspartate amino transferase(AST),total cholesterol(CHOL),triglyceride(TG),high-density lipoprotein cholesterol(HDL-c)and low density lipoprotein cholesterol(LDL-c)level were observed.Liver index and insulin resistance index(HOMA-IR)were calculated.The activities of TLR4 and P-ERK1/2 proteins in liver tissues were detected by Western blot and RT-PCR.Results:Compared with the control group,the levels of 2 hBG,Fins,HOMA-IR,ALT,AST,TG,CHOL and LDL-C,the Liver index and pathological score were significantly increased in the model group,the level of HDL-c was significantly decreased,and mRNA and protein expression levels of TLR4 and p-ERK1/2 were significantly up-regulated in the model group.Compared with the model group,the levels of 2 hBG,Fins,HOMA-IR,ALT,AST,TG,CHOL,LDL-C,liver index and histopathological score in Zhibitai groups(200 mg/kg,100 mg/kg)were significantly reduced,the level of HDL-c and ratio of AST/ALT were significantly increased,the mRNA and protein expression levels of TLR4 and p-ERK1/2 were significantly decreased.Conclusion:Zhibitai can affect the MAPK-ERK-TLRs pathway by down-regulating the expressions of TLR4 and P-ERK1/2 proteins,it can inhibit the transduction of inflammatory signaling pathway,prevent the occurrence and development of inflammation,regulate blood lipids,and antagonize insulin resistance to protect the liver.