Mechanism of celastrol in improving liver fibrosis in type 2 diabetic rats
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<O.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.