雷公藤红素改善2型糖尿病大鼠肝纤维化的机制探讨  

Mechanism of celastrol in improving liver fibrosis in type 2 diabetic rats

作　　者：周巧逢 雷敏 郭西英 何昂 刘秀芬[2] 李敏才[2,3] ZHOU Qiaofeng;LEI Min;GUO Xiying;HE Ang;LIU Xiufen;LI Mincai(College of Pharmacy,Hubei University of Science and Technology,Xianning 437100,Hubei,China)

机构地区：[1]湖北科技学院药学院,湖北咸宁437100 [2]湖北科技学院医药研究院,湖北咸宁437100 [3]湖北科技学院病理学教研室,湖北咸宁437100

出　　处：《皖南医学院学报》2024年第2期121-125,共5页Journal of Wannan Medical College

基　　金：湖北省实验动物资源开发及利用省级科技创新项目(2021DFE025);糖尿病心脑血管病变湖北省重点实验室开放基金项目(2020TNB09)。

摘　　要：目的:探讨雷公藤红素(CEL)对2型糖尿病(T2DM)所致的肝纤维化的改善作用及其内在机制。方法:建立T2DM大鼠模型,将24只雄性SD大鼠分成4组,即空白对照(Con)组、对照给药(CEL)组、模型(T2DM)组和模型给药(T2DM+CEL)组。每周监测各组大鼠体质量和空腹血糖(FBG),T2DM造模成功2周后给予CEL 3 mg/(kg·d)灌胃,1次/天持续12周,检测血清空腹胰岛素(FINS)、谷草转氨酶(AST)、谷丙转氨酶(ALT)及肝组织羟脯氨酸(Hyp)水平。肝组织切片行Masson染色和天狼猩红染色,观察肝组织纤维化程度和胶原蛋白沉积。Western blot检测肝组织α-SMA、Collagen Ⅰ、Collagen Ⅲ、沉默信息调节因子1(SIRT1)、TGF-β1和Smad3的蛋白表达变化。结果:与Con组比较,T2DM组大鼠24 h尿量、FBG、FINS、AST、ALT、Hyp水平均升高(P<0.001);胶原容积分数(CVF)升高(P<0.001);肝组织α-SMA、Collagen Ⅰ、Collagen Ⅲ、TGF-β1、Smad3蛋白表达量均升高(P<0.05),SIRT1蛋白表达量降低(P<0.01)。与T2DM组相比,给予CEL后大鼠24 h尿量、FBG、FINS、AST、ALT、Hyp水平均降低(P<0.05);肝组织胶原沉积减少,纤维化状况改善;肝组织SIRT1表达升高(P<0.05),纤维化相关蛋白表达水平均降低(P<0.05)。结论:CEL可减轻T2DM大鼠肝脏组织的纤维化,其机制可能与调控SIRT1、抑制TGF-β/Smad信号通路有关。Objective:To investigate the ameliorative effect of celastrol(CEL)on and the underlying mechanism in type 2 diabetes mellitus(T2DM)induced liver fibrosis.Methods:T2DM model was established.Twenty-four male SD rats were divided into blank control group(Con group),control administration group(CEL group),model group(T2DM group)and model administration group(T2DM+CEL group).The body weight and fasting blood glucose(FBG)of rats in each group were monitored weekly,and CEL[3mg/(kg·d)]was given by gavage two weeks after the successful modeling of T2DM,once a day for 12 weeks,and the levels of serum fasting insulin(FINS),aspartate aminotransferase(AST),alanine aminotransferase(ALT)and hydroxyproline(Hyp)were measured.Masson staining and Sirius Red staining were performed on liver sections to observe the extent of fibrosis and collagen deposition.α-SMA,Collagen Ⅰ,Collagen Ⅲ,SIRT1,TGF-β1 and Smad3 protein expression changes were detected by Western-blot.Results:Compared with the Con group,24-hour urine volume,FBG,FINS,AST ALT and Hyp levels were significantly higher in the T2DM group(P<0.001).The collagen volume fraction(CVF)was remarkably higher(P<0.001),and the expression of α-SMA,Collagen Ⅰ,Collagen Ⅲ,TGF-β1 and Smad3 proteins in liver tissues were significantly higher(P<0.05),yet the expression of SIRT1 protein was markedly lower(P<0.01).Compared with the T2DM group,the levels of 24-hour urine volume,FBG,FINS,AST ALT and Hyp in rats were significantly reduced after CEL administration(P<0.05),and the collagen deposition in liver tissues was reduced and the fibrosis status was significantly improved.SIRT1 in liver tissues was highly expressed(P<0.05),and the expression of fibrosis-related proteins was notably reduced(P<0.05).Conclusion:Celastrol can reduce fibrosis in liver tissues of type 2 diabetic rats.The mechanism may be related to the regulation of SIRT1 and inhibition of TGF-β/Smad signaling pathway.

关 键 词：雷公藤红素 2型糖尿病 肝纤维化 沉默信息调节因子1 TGF-Β/SMAD 

分 类 号：R587.1[医药卫生—内分泌] R-332[医药卫生—内科学] R285.5[医药卫生—临床医学]