齐多夫定对小鼠糖脂代谢平衡的影响及作用机制

Effects and mechanism of zidovudine on glucolipid metabolic balance in mice

研究核苷类抗病毒药物齐多夫定(zidovudine,AZT)对小鼠整体代谢及肝脏糖脂代谢平衡的影响。雄性ICR小鼠连续灌胃齐多夫定12周,每天记录小鼠的饮水量及摄食量。检测给药12周后不同禁食时间血清葡萄糖(GLU)、甘油三酯(TG)水平以及血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平,进行糖耐量实验(OGTT)和胰岛素耐量实验(ITT);HE染色观察肝脏病理学变化;RT-PCR检测葡萄糖转运蛋白(Glut2)、肉碱棕榈酸转移酶(Cpt1α)、中链酰基辅酶A脱氢酶(Mcad)以及磷酸烯醇式丙酮酸羧激酶(Pepck)、葡萄糖-6-磷酸酶(G6pase)的基因水平;Westernblot检测肝脏胰岛素信号Akt、P-Akt及Glut2、Mcad、Cpt1α的蛋白水平。结果显示,齐多夫定导致禁食后脂代谢能力显著下降,糖耐量受损,肝细胞体积增大,显著增加肝脏TG、非酯化脂肪酸(NEFA)含量,提高Glut2基因表达,下调脂肪酸氧化代谢基因Cpt1α、Mcad和糖异生相关基因水平,以及下调Cpt1α的蛋白表达。实验结果提示齐多夫定能够引起禁食后糖脂代谢紊乱,且呈一定的剂量依赖性。

To study the effects of nucleoside antiviral drug zidovudine(AZT)on the flexibility of global metabolism and liver glucolipid metabolic balance in mice,male ICR mice were given zidovudine intragastric administration for 12 weeks,and their water and food intake was recorded daily.Serum glucose(GLU)and triglyceride(TG)levels and serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected after 12 weeks of administration.Oral glucose tolerance test(OGTT)and insulin tolerance test(ITT)were performed.HE staining was used to observe the pathological changes of liver.The gene levels of glucose transporter(Glut2),carnitine palmitate transferase(Cpt1α),medium chain acyl-coa dehydrogenase(Mcad),phosphoenolpyruvate carboxykinase(Pepck)and glucose-6-phosphatase(G6pase)were detected by RT-PCR.Western blot was used to detect the protein levels of insulin signaling Akt,P-Akt,Glut2,Mcad and Cpt1αin liver.The results showed that zidovudine significantly decreased lipid metabolism,impaired glucose tolerance,increased liver cell volume,significantly increased liver triglyceride(TG)and non-esterified fatty acid(NEFA)content,increased Glut2 gene expression,down-regulated fatty acid oxidative metabolism genes Cpt1α,Mcad and gluconeogenesis related genes after fasting,and down-regulated protein expression of Cpt1α.The results suggest that zidovudine can induce the disorder of glucose and lipid metabolism after fasting in a dose-dependent manner.