The Effects Of MEK Inhibitor PD98059 And Astragalus Membranaceus Extraction On Expression Of Sterol Regulatory Element Binding Protein-1,suppressor Of Cytokine Signaling-3 In Rats With Nonalcoholic Fatty Liver Disease

Objective(1)To observe sterol regulatory element binding protein-1(SREBP-1),suppressor of cytokine signaling-3(SOCS-3) expression in rat NAFLD induced by high-fat diet.( 2 ) To investigate the effect of MEK inhibitor PD98059 and astragalus membranaceus extraction (AME) on the expression of Sterol Regulatory Element Binding Protein-1(SREBP-1),suppressor of cytokine signaling-3(SOCS-3) in Rats with nonalcoholic fatty liver disease (NAFLD).Methods(1)The part of MEK inhibitor PD98059 intervention NAFLD animal model was duplicated with high fat diet. Thirty-two male Wister rats were randomly divided into normal control group ( group N) , PD98059 and common diet group ( group P) , high-fat model group ( group M) and PD98059 and high-fat diet group ( group PM) with 8 for each group. At the end of 4, 6, and 8 weeks, the rats were given a tail vein injection of either PD98059 (0.3 mg/ kg, group P and group PM) or the relative solvent ( group N and group M).After ten weeks, all the rats were sacrificed. The serum alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , triglycerides( TG) , total cholesterol ( TC) and the hepatic TG, TC were measured. The pathological changes in rat liver were observed, the expression of SREBP-1 and SOCS-3 in liver was detected by immunohistochemical method.(2)The part of AME intervention Forty male Wister rats were randomly divided into normal control group ,model group , low ,moderate and high dose of AME-treated group with 8 for each group. Besides fed with high fat diet, the rats in treatment group were intervened by different dose of AME every day. After ten weeks, all the rats were sacrificed. The serum alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , triglycerides( TG) , total cholesterol ( TC) and the hepatic TG, TC were measured. The pathological changes in rat liver were observed, the expression of SREBP-1 and SOCS-3 in liver was detected by immunohistochemical method.Results(1)The part of MEK inhibitor PD98059 intervention The rat NAFLD model was well duplicated with high-fat diet after 10 weeks. Compared with group N, the group M developed over 30% steatosis, with inflammation cell infiltration and necrosis(P<0.01), the serum ALT, AST, TG, the level of liver tissue homogenates TC, TG(P<0.01)and the expression of SREBP-1, SOCS-3 in liver markedly increased(P<0.01). Compared with group M, the expression of SREBP-1 and SOCS-3(P<0.01), the serum ALT, TC, TG and the level of liver tissue homogenates TG, TC(P<0.01)decreased in group PM, while the histopathological change in liver of group PM ameliorated(P<0.05). Liver TG was positively correlated with the SREBP-1 and SOCS-3(r=0.756, P<0.05 ;r=0.776 , P<0.05).Liver TC was positively correlated with the SREBP-1 and SOCS-3(r=0.980,P<0.01; r=0.981,P<0.01).SREBP-1 was positively correlated with SOCS-3(r=0.960, P<0.01)in group M.(2)The part of AME intervention Compared with normal control group, the serum ALT, AST, TC and the hepatic TG, TC in model group were markedly highe(rP<0.01). The model group presented with steatosis, inflammation or necroinflammation(P<0.01). Compared with the model group, the serum ALT, AST, TG, TC, and the hepatic TG, TC decreased( P<0.01,P<0.05), while the pathological changes in liver were improved in AME-treated groups( P<0.01,P<0.05). The SREBP-1 and SOCS-3 expression in model group increased significantly comparied with normal group(P<0.01)and the SREBP-1 and SOCS-3 expression in AME-treated groups reduced significantly compared with model group(P<0.01). Liver TG was positively correlated with the SREBP-1 and SOCS-3(r=0.948,P<0.01; r=0.988 P<0.01).Liver TC was positively correlated with the SREBP-1 and SOCS-3(r=0.987, P<0.01,; r=0.965, P<0.01).SREBP-1 was positively correlated with SOCS-3(r=0.960,P<0.01)in the model group.Conclusion(1)the expression of SREBP-1 and SOCS-3 increased in rat NAFLD induced by high-fat diet. Liver TG was positively correlated with the SREBP-1 and SOCS-3,Liver TC was positively correlated with the SREBP-1 and SOCS-3,SREBP-1 was positively correlated with SOCS-3.(2)MEK inhibitor PD98059 reduce the expression of SREBP-1 and SOCS-3 in rat NAFLD induced by high-fat diet . It suggests that MEK/ERK signal pathway play an important role in the expression of SREBP-1 and SOCS-3 in rat NAFLD induced by high-fat diet .(3) AME exerts protective effects against NAFLD in rats induced by high fat diet possibly through its regulating the lipid metabolism and inhibiting the expression of SREBP-1 and SOCS-3.