目的：观察利拉鲁肽对高脂喂养大鼠内质网应激标记蛋白葡萄糖调节蛋白（GRP78）及c-Jun氨基端激酶（JNK）蛋白的表达及肝脏脂质沉积的影响。方法以高脂饮食喂养方法建立IR大鼠模型，成模后随机分为对照组（Con）、高脂组（HFD）、低剂量利拉鲁肽组（LL）、高剂量利拉鲁肽组（HL）。药物干预2周后，每组随机取5只行高胰岛素-正葡萄糖钳夹实验。结果与HFD和LL组比较，HL组肝脏内TG（LTG）降低（P＜0．05）。Western blot 结果显示，与 HFD和LL 组比较，HL 组GRP78[（1．24±0．13）vs（0．97±0．04）vs（0．62±0．17），P＜0．05]及JNK下降[（0．38±0．01）vs（0．21±0．01）vs （0．12±0．02），P＜0．05]。电镜结果显示，HFD组肝细胞内有大量脂质，粗面内质网明显扩张，脱颗粒现象明显；HL组肝细胞内无脂质蓄积存在，粗面内质网扩张及脱颗粒现象得到显著缓解。相关分析结果显示，GRP78、JNK蛋白表达量与FFA、LTG呈正相关，与葡萄糖输注率（GIR）呈负相关。结论利拉鲁肽可呈浓度依赖性改善高脂喂养大鼠脂代谢异常和肝脏脂质沉积，减轻IR，其作用机制可能与肝脏GRP78／JNK通路受抑有关。%Objective To investigate the effect of Liraglutide on the expressions of endoplasmic reticulum stress marker proteins [glucose regulated proteins 78 (GRP78 )and c-Jun N-terminal kinase (JNK)]and the accumulation of lipids in the liver of high-fat diet rats. Methods The insulin-resistant (IR)models were induced by high-fat diet. The modeled rats were divided into 4 groups:normal control group (NC,n= 1 1 ),high-fat diet group (HFD,n= 1 1 ),low dose liraglutide group (LL,n= 1 1 )and high dose liraglutide group (HL,n= 1 1 )for 2 weeks of drug intervention. Five rats were randomly chosen in each group and treated with hyperinsulinemic-euglycemic clamp test to assess insulin sensitivity. Results (1)Compared with HFD and LL groups,the TG of liver (LTG)in HL group was significantly lower (P<0. 05). Western blot test showed that,compared with HFD and LL groups,both of the expressions of GRP78[(1. 24±0. 13)vs (0. 97±0. 04)vs (0. 62±0. 17)and JNK [(0. 38±0. 01)vs (0. 21±0. 01)vs (0. 12±0. 02)]were significantly lower (P<0. 05). (2)Electron microscopy showed that HFD group presented with larger number of lipid droplets in cytoplasm and more obvious rough endoplasmic reticulum (RER)expansion and degranulation than HL group. (3)The levels of GRP78 and JNK protein expression were positively correlated with FFA and the TG in liver but negatively correlated with glucose infusion rate (GIR ). Conclusion Liraglutide shows a dose-dependent manner to ameliorate lipid metabolism disorder,reduce lipid accumulation and improve insulin resistance in the liver of high-fat diet rats,which may be related to the regulation of GRP78/JNK pathway.
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