地奥心血康激活IRS-1/PI3K/Akt信号通路改善非酒精性脂肪性肝炎小鼠胰岛素抵抗的实验研究

Di'ao Xinxuekang activates IRS-1/PI3K/Akt signal pathway to improve insulin resistance in nonalcoholic fatty hepatitis mice

目的:研究地奥心血康(DXXK)对非酒精性脂肪性肝炎(NASH)小鼠胰岛素抵抗的影响及作用机制。方法:C57BL/6J小鼠随机分为正常组和造模组,造模组高脂饲料饲喂16周后随机分为模型组、吡格列酮组(6.0 mg·kg^(-1)·d^(-1)),DXXK高、中、低(200、60、20 mg·kg^(-1)·d^(-1))剂量组,每组8只,灌胃给药连续8周。检测小鼠体质量、活动度、脂肪质量、空腹血糖(FBG)、血清胰岛素(FINS)、总胆固醇(TC)、甘油三酯(TG)、天冬氨酸转氨酶(AST)、丙氨酸氨基转移酶(ALT)水平及肝脏中的TC、TG含量;口服葡萄糖耐量实验(OGTT)、腹腔胰岛素耐量实验(IPITT),计算胰岛素抵抗指数(HOMA-IR)、胰岛素敏感指数(ISI)、OGTT和IPITT的曲线下面积(AUC);HE染色观察肝脏病理、油红O染色观察肝脏脂质蓄积情况;Western blot法检测肝脏组织IRS-1/PI3K/Akt信号通路中相关蛋白及下游靶标甾醇调节元件结合蛋白1c(SREBP-1c)蛋白水平。结果:与模型组比较,DXXK组和吡格列酮组小鼠的体质量、脂肪质量、FBG、FINS、HOMA-IR、ISI、TC、TG、AST、ALT水平、OGTT和IPITT的AUC均显著降低(P<0.05,P<0.01),活动度显著升高,肝脏脂质沉积和肝功能异常明显改善(P<0.05,P<0.01),肝细胞脂肪变性和气球样变明显减轻,肝脏p-IRS-1/IRS-1、PI3K、p-AKT/AKT蛋白表达显著上调,SREBP-1c蛋白表达显著下降(P<0.05,P<0.01)。结论:DXXK可以改善NASH小鼠的胰岛素抵抗,其作用机制可能与激活IRS-1/PI3K/Akt信号通路有关。

AIM:To study the effect and mecha-nism of Di'ao Xinxuekang(DXXK)on insulin resis-tance in nonalcoholic steatohepatitis(NASH)mice.METHODS:C57BL/6J mice were randomly divided into normal group and model group.After 16 weeks of high-fat diet,the model group was ran-domly divided into model group and Pioglitazone group(6.0 mg·kg^(-1)·d^(-1)),DXXK high,medium,and low(200,60,20 mg·kg^(-1)·d^(-1))dose groups,with 8 animals in each group,and were administered by gavage for 8 consecutive weeks.The body weight,activity,fat mass,fasting blood sugar(FBG),serum insulin(FINS),total cholesterol(TC),triglyceride(TG),aspartic acid transaminase(AST),alanine ami-no transferase(ALT),and the contents of TC and TG in the liver were measured;oral glucose tolerance test(OGTT),intraperitoneal insulin tolerance test(IPITT),calculate insulin resistance index(HOMA-IR),insulin sensitivity index(ISI),area under curve(AUC)of OGTT and IPITT.HE staining was used to observe liver pathology,and Oil Red O staining was used to observe liver lipid accumulation.Western blot was used to detect the related proteins and downstream target SREBP-1c protein in the IRS-1/PI3K/Akt signaling pathway in liver tissue.RESULTS:Compared with the model group,the body weight,fat mass,FBG,FINS,HOMA-IR,ISI,TC,TG,AST,ALT levels,AUC of OGTT and IPITT in DXXK group and pioglitazone group were significantly reduced,sig-nificant increase in activity,liver lipid deposition and liver function abnormalities were significantly improved,hepatocyte steatosis and ballooning were significantly reduced,and liver p-IRS-1/IRS-1,PI3K,p-AKT/AKT protein expression was significant-ly increased,SREBP-1c protein expression was sig-nificant decrease.CONCLUTION:DXXK can improve insulin resistance in NASH mice,and its mechanism of action may be related to the activation of the IRS-1/PI3K/Akt signaling pathway.