Therapeutic Effect Of Staphylokinase And Staphylokinase Derivative On Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD), defined as liver fat content exceeding 5%, occurs in the absence of significant alcohol abuse, considering a metabolic syndrome. It has been found that 14%-33% of the general population suffers from NAFLD in all age groups. The clinicopathologic spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), simple steatosis is generally nonprogressive whereas NASH can lead to cirrhosis, hepatocellular carcinoma, and liver failure.Staphylokinase (SAK) is a protein of single chain polypeptide secreted by a lysogenic strain of Staphylococcus aureus. SAK of M.W. 15.5kD consists of 136 amino acid residues containing 45 charged amino acid residues, without either cysteine or disulfide bond. Staphylokinase (SAK), a type of thrombolytic drug, which is not an enzyme but can form a 1:1 stoichiometric complex with plasmin(ogen) that activates other plasminogen molecles and is an ideal thrombolytic agent, and has been shown to affect fibrin lysis and degradate fibrin. Our studies found that SAK might participate in the metabolism of lipid, therefore, we raised the question whether SAK can change the symptoms of Non-alcoholic fatty liver disease or not. The engineering E.coli strain harboring the mutant SAK with introduced RGD sequence and 12 amino acid residuces at the C turnminus and without antigenic epitopes was obtained in our early studies. This engineering strain was expressed and purified. The obtained product was named Staphylokinase derivative, with a purity of 95%, and proved bioactive by cell assay. The main results are as follows:1 The rat model of non-alcoholic fatty liver diseaseThe non-alcoholic fatty liver rat model was generated by feeding high-energy diet. The result indicated that the body weight and the liver index of the rats fed on high-fat diet increased quickly; Serum total cholesterol (CHO), triglycerides (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD) and malondialdehyde (MDA) were significantly high in high-energy diet fed group; The degree of liver fatty degeneration was severer in high-energy diet fed group than in control group, and the level of PPAR-a was increased in high-energy diet fed. The result indicated that non-alcoholic fatty liver disease model can be successful induced by high fat diet.2 Therapeutic Effect of Staphylokinase on Non-alcoholic Fatty Liver Disease The NAFLD model were induced by high-energy diet, and then treated with SAK intravenously. The serum AST, TG, CHO, LDL, MDA in the SAK treated group were markedly lower, while the expression of PPAR-a mRNA was increased. Staphylokinase ameliorates the degree of Non-alcoholic fatty liver disease in rat model, the mechanisms of treating Non-alcoholic fatty liver disease may be related to promoting expression of PPAR-a.3 Therapeutic Effect of Staphylokinase derivative on Non-alcoholic Fatty Liver DiseaseThe NAFLD model were also induced by high-energy diet, and then treated with SAK derivative intravenously and Simvastatin through intragastric administration. The serum AST, TG, CHO, LDL, MDA in the SAK derivative and Simvastatin treated group were markedly lower, while the expression of PPAR-a and ADIPOR2 mRNA were increased, but the SAK derivative treated group and the Simvastatin treated group didn't have significantly difference. Staphylokinase derivative and Simvastatin ameliorates the degree of Non-alcoholic fatty liver disease in rat model, the mechanisms of treating Non-alcoholic fatty liver disease may be related to promoting expression of PPAR-a and ADIPOR2.