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目的观察利拉鲁肽对高脂喂养大鼠胰腺GRP78、转录活化因子4(ATF4)、CCAAT区/增强子结合蛋白同源蛋白(CHOP)、TRB3蛋白和mRNA表达情况,探讨利拉鲁肽对高脂喂养大鼠胰腺ATF4/CHOP通路的影响。方法将雄性Wistar大鼠44只分为对照组、高脂组、干预组1、干预组2,每组11只,对照组给予普通饮食,其余3组给予高脂饮食喂养8周后,干预组1给予利拉鲁肽100μg·kg-1·d-1皮下注射;干预组2给予利拉鲁肽200μg·kg-1·d-1皮下注射。药物干预2周后处死,每组取5只大鼠行清醒状态下高胰岛素-正葡萄糖钳夹试验计算葡萄糖输注率(GIR),测定其余大鼠空腹血糖(FBG)、空腹胰岛素(FINS)、血清游离脂肪酸(FFA)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDLC),计算胰岛β细胞功能指数(HOMA-β),Western blot和Realtime-PCR技术检测胰腺GRP78、ATF4、CHOP和TRB3蛋白及mRNA的表达。结果与对照组相比,高脂组FBG、FFA、TC、FINS、TG、LDL-C水平显著升高,HDL-C、GIR和HOMA-β明显下降(P<0.05或P<0.01),与高脂组相比,干预组2HDL-C、GIR和HOMA-β升高(P<0.05或P<0.01),其余指标明显下降;与干预组1相比,干预组2的血FGB、FFA、TC下降,GIR和HOMA-β升高(P<0.05)。与对照组相比,高脂组GRP78、ATF4、CHOP和TRB3蛋白及mRNA的表达明显升高;与高脂组相比,干预组1与干预组2随利拉鲁肽浓度升高,GRP78、ATF4、CHOP和TRB3蛋白及mRNA表达逐渐下降。结论利拉鲁肽可呈浓度依赖性改善高脂喂养大鼠胰岛素抵抗及保护胰岛β细胞,其作用机制可能涉及胰腺内质网ATF4/CHOP通路。
Objective To observe the expression of GRP78, ATF4, CHOP, TRB3 protein and mRNA in the pancreas of high fat diet rats after liraglutide treatment, and to investigate the effects of liraglutide on Effect of High Fat Diet on ATF4 / CHOP Pathway in Rat Pancreas. Methods Forty-four male Wistar rats were divided into control group, high fat diet group, intervention group 1, intervention group 2, each group 11, control group given normal diet, and the remaining three groups were given high fat diet for 8 weeks, 1 given liraglutide 100μg · kg-1 · d-1 subcutaneous injection; intervention group 2 given liraglutide 200μg · kg-1 · d-1 subcutaneous injection. Two weeks after drug intervention, rats were sacrificed, and 5 rats in each group were given glucose-infusion rate (GIR), fasting blood glucose (FBG), fasting insulin (FINS) , Serum free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDLC) β), Western blot and Realtime-PCR were used to detect the protein and mRNA expression of GRP78, ATF4, CHOP and TRB3 in pancreas. Results Compared with the control group, the levels of FBG, FFA, TC, FINS, TG and LDL-C were significantly increased and the levels of HDL-C, GIR and HOMA-β were significantly decreased in hyperlipidemia group (P <0.05 or P <0.01) Compared with the control group, the levels of 2HDL-C, GIR and HOMA-β in the intervention group were significantly increased (P <0.05 or P <0.01) TC decreased, GIR and HOMA-β increased (P <0.05). Compared with the control group, the expressions of GRP78, ATF4, CHOP and TRB3 protein and mRNA in the hyperlipidemia group were significantly increased. Compared with the hyperlipidemia group, the concentrations of liraglutide in the intervention group 1 and the intervention group 2 were increased, the expressions of GRP78, ATF4, CHOP and TRB3 protein and mRNA expression decreased gradually. Conclusion Liraglutide can ameliorate the insulin resistance and protect the islet β cells in a concentration-dependent manner in rats fed with high fat diet. The mechanism may be related to the ATF4 / CHOP pathway of the pancreatic endoplasmic reticulum.