胰升糖素样肽1类似物对非酒精性脂肪肝大鼠IRE1α-JNK通路的干预效应

The intervention of glucagon-like peptide 1 analogue in IRE1α-JNK signaling pathway of rats with non- alcoholic fatty liver disease

目的探讨非酒精性脂肪肝（NAFLD）大鼠肝脏组织内质网应激（ERs）相关因子肌醇需求激酶1α（IRE1α）、磷酸化1RE1α（p-IRE1α）、c-jun氨基末端激酶（JNK）、磷酸化JNK（p-JNK）的表达情况，观察胰升糖素样肽1（GLP-1）类似物的干预作用。方法将40只雄性sD大鼠分为正常饮食组（n=15）和高脂饮食组（n=25），喂养12周后，每组取5只评估NAFLD大鼠模型的建立，再将高脂饮食组大鼠分为高脂饮食组（HF，n=10）和GLP—1组（HG，n=10），分别以生理盐水及GLP-1类似物干预4周，测定大鼠体重及生化指标，Western印迹法检测肝组织IRE1α、p-IRE1α、JNK、p-JNK的蛋白表达水平。结果HF组大鼠的体重、血清甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、丙氨酸转移酶（ALT）、天冬氨酸转移酶（AST）较正常饮食组明显升高（均P〈0．01），高密度脂蛋白胆固醇（HDL-C）明显降低（P〈0．01），p-IRE1α/IRE1α及p-JNK／JNK升高（P〈0．05及P〈0．01），而高脂喂养的大鼠经GLP-1类似物干预后，体重、TG、TC、LDL-C、AST、ALT明显降低（P〈0．05或P〈0．01），HDL-C明显升高（P〈0．01），p-IRE1α/IRE1α及P—JNK／JNK降低（P〈O．05及P〈0．01）。结论GLP-1类似物可能通过调节ERs相关IRE1α-JNK通路改善肝脏脂肪变性。

Objective To explore the expressions of endoplasmie retieulum stress （ERs） related factors including inositol requiting enzyme-1 α （ IRE 1 α）, p-IRE 1α, c-jun N-terminal Kinase （ JNK）, and p-JNK in rats with non-alcoholic fatty liver disease, and to investigate the effect of intervention with glucagon-like peptide 1 （ GLP-1 ） analogue. Methods Forty male Sprague-Dawley rats were divided into normal chow group（ n = 15 ） and high-fat diet group（ n = 25 ）. After 12 weeks, 5 rats of each group were used to assess the establishment of rat models with non- alcoholic fatty liver disease. Then the high-fat diet group rats were divided into high-fat diet group （ HF, n = 10 ） and GLP-1 group（ HG, n= 10） and treated with normal saline and GLP-1 analogue for 4 weeks respectively. Body weight and biochemical markers in rats were measured. The expressions of IRE1α, p-IRE1α, JNK, and p-JNK were measured by Western blot. Results Compared with the NC group, the levels of body weight, plasma triglyceride （TG） , total cholesterol （ TC ） , low density lipoprotein-cholesterol （ LDL-C ） , alanine aminotransferase （ ALT ） and aspartate aminotransferase （AST） in HF group were significantly higher （ all P 〈 0.01 ）, high density lipoprotein- cholesterol （ HDL-C ） was decreased （ P〈0.01 ）, and p-IRE1α/IRE1 α and p-JNK/JNK were increased （ P〈 0.05 and P〈0.01 ）. After GLP-1 treatment, body weight, plasma TG, TC, LDL-C, AST, ALT in HF group were significantly lowered（ P〈0.05 or P〈0.01 ）, HDL-C was increased（ P〈0.01 ） , p-IRE1 α/IRE1 α and p-JNK/JNK were decreased （P〈0.05 and P〈0.01 ）. Conclusion GLP-1 analogue may improve hepatic steatosis via regulating ERs related IRE1 α-JNK signaling pathway.