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目的通过自发性2型糖尿病(type 2 diabetes mellitus,T2DM)小鼠模型,观察牛磺熊脱氧胆酸(tauroursodeoxycholic acid,TUDCA)对T2DM小鼠肝损伤的影响。方法将db/db小鼠和db/m(lean)小鼠分别随机分成TUDCA处理组和溶剂(vehicle,VEH)对照组。TUDCA处理组给予500mg/kg/day灌胃,连续2周,溶剂对照组采用同样方法给予同样剂量的PBS溶液。观察动物空腹血糖、甘油三酯(TG)、总胆固醇(TC)、谷丙转氨酶(ALT)、谷草转氨酶(AST)变化,并检测肝组织丙二醛(MDA)、活性氧(ROS)的含量、超氧化物歧化酶(SOD)、黄嘌呤氧化酶(XOD)的活力和甘油三酯、胆固醇含量;光镜和透射电镜观察肝脏组织形态和超微结构改变。结果与lean+VEH组相比,db/db+VEH组小鼠空腹血糖、血浆ALT、AST、TC、TG、肝脏组织TC、TG、MDA、XOD、ROS含量均显著升高,SOD活性明显降低(均P<0.05);与db/db+VEH组相比,db/db+TUD组小鼠血浆ALT、AST水平降低(P<0.05),TG、TC虽有些变化,但差异无统计学意义。肝脏组织TC、TG、MDA、XOD、ROS含量减少(均P<0.05),SOD活性增高(P<0.05),光镜下可见db/db+VEH组小鼠肝脏组织炎细胞浸润、水肿,胞质疏松淡染和气球样变,细胞排列紊乱拥挤,肝窦受压变窄,并可见融合的脂滴;透射电镜下肝细胞常、异染色质分布不均,核固缩比较明显,可见脂滴沉积,线粒体肿胀,内质网扩张。与db/db+VEH组相比,db/db+TUD组小鼠光镜下肝细胞水肿减轻,炎细胞浸润减少,偶见脂肪变性;透射电镜下肝细胞染色质分布均匀,内质网扩张减轻,偶见脂滴。结论内质网应激抑制剂TUDCA对2型糖尿病小鼠肝脏有保护作用,其机制与减轻氧化应激反应有关。
Objective To investigate the effect of tauroursodeoxycholic acid (TUDCA) on hepatic injury in T2DM mice via a mouse model of type 2 diabetes mellitus (T2DM). Methods db / db mice and db / m (lean) mice were randomly divided into TUDCA treatment group and vehicle (VEH) control group. TUDCA treatment group was given 500mg / kg / day gavage for 2 consecutive weeks, the solvent control group using the same method given the same dose of PBS solution. The changes of fasting blood glucose, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed and the content of malondialdehyde (MDA) and reactive oxygen species (ROS) , Superoxide dismutase (SOD), xanthine oxidase (XOD) and triglyceride and cholesterol content were observed. The morphological and ultrastructural changes of liver tissue were observed under light microscope and transmission electron microscope. Results Compared with lean + VEH group, the levels of fasting blood glucose, plasma ALT, AST, TC, TG, liver TC, TG, MDA, XOD and ROS in db / db + VEH group were significantly increased (All P <0.05). Compared with db / db + VEH group, the levels of plasma ALT and AST in db / db + TUD mice decreased (P <0.05), while there were no significant differences in TG and TC . The contents of TC, TG, MDA, XOD and ROS in the liver decreased (all P <0.05) and the activity of SOD increased (P <0.05). The inflammatory cells infiltration and edema in the db / db + VEH group Loose light quality and balloon-like changes, crowding cells disorder, sinusoidal compression narrowing, and see the fusion of lipid droplets; under transmission electron microscopy often, heterochromatin uneven distribution of nuclear pyknosis more obvious, visible fat Deposition, mitochondria swelling, endoplasmic reticulum dilatation. Compared with the db / db + VEH group, the db / db + TUD group had less hepatocellular edema and less inflammatory cell infiltration in the light microscope, and the fatty degeneration was observed occasionally. The distribution of chromatin in hepatocytes was homogeneous under transmission electron microscope and the endoplasmic reticulum was dilated Reduce, occasionally lipid droplets. Conclusion Endoplasmic reticulum stress inhibitor TUDCA has a protective effect on the liver of type 2 diabetic mice, and its mechanism is related to the reduction of oxidative stress.