Study On The Mechanism Of Oleuropein In Improving Liver Fibrosis

Objective Studies have shown that epithelial-mesenchymal transition(EMT)is one of the important sources of extracellular matrix(ECM)production in liver tissue,which can accelerate liver fibrosis through a variety of signal pathways.Previous studies found that in the mouse hepatocyte EMT model,TGF-β 1/p38 MAPK signaling pathway promotes the progression of liver fibrosis by up regulating ELK-3 induced EMT.Oleuropein(OL)has anti-cancer,liver protection,anti-virus,anti-inflammatory and other effects.However,there are few reports on the correlation between oleuropein and ELK-3 in the process of liver fibrosis.This study was to investigate the effect of oleuropein on liver fibrosis and its mechanism.Methods Forty SD rats were randomly divided into normal control group,model group,low dose of oleuropein group(10 mg/kg)and high dose of oleuropein group(40 mg/kg)with 10 rats in each group.Except the normal control group,the rats in the other groups were intraperitoneally injected with 50% CCl4 olive oil solution twice a week for 8 weeks(1 ml/kg)to establish the liver fibrosis model.From the 5th week of modeling,rats in each administration group were given corresponding oleuropein by gavage,while rats in normal control group and model group were given DMSO solution of equal volume by gavage once a day until the 8th week.The liver index,AST,ALP,HA levels in serum and Hyp levels in liver tissue were detected.The histopathological changes of rat liver tissue were observed by HE and Masson staining.The protein levels of α-SMA,p38,ELK-3,E-cadherin and Vimentin in liver tissues were determined by Western blot analysis.Results Compared with the normal control group,the liver index and serum AST,ALT and HA levels of rats in the liver fibrosis model group were significantly increased(P<0.05).Compared with the model group,the liver index and serum AST,ALT and HA levels of rats in each dose of oleuropein group were significantly reduced(P<0.05).Compared with the normal control group,the Hyp level in the liver tissue of the model group was significantly increased(P<0.05).Compared with the model group,the level of Hyp in liver tissue of rats in each dose group of oleuropein was significantly reduced(P<0.05).Compared with the normal control group,the liver tissue of the model group had obvious liver injury,abnormal cell morphology,inflammatory cell infiltration,and significantly increased collagen deposition area percentage(P<0.05).Compared with the model group,the degree of liver injury and inflammatory infiltration in liver tissue of rats in each dose group of oleuropein was reduced,and the percentage of collagen deposition area was significantly reduced(P<0.05).Compared with the normal control group,the expression levels of α-SMA,ELK-3,Vimentin protein and p38 phosphorylation in the liver tissues of the model group were significantly increased(P<0.05),while the expression levels of E-cadherin protein were significantly decreased(P<0.05).Compared with the model group,the expression levels of α-SMA,ELK-3,Vimentin protein and p38 phosphorylation in liver tissues of rats at different doses of oleuropein were significantly reduced(P<0.05),while the expression level of E-cadherin protein was significantly increased(P<0.05).Conclusions Oleuropein prevents epithelial-mesenchymal transition by down regulating p38 MAPK/ELK-3 signal pathway,and then improves the process of liver fibrosis.