Therapeutic Effect Of Exenatide On Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) mainly refers to an kind of disease that lipid metabolism disorders of liver cells causes fatty degeneration and deposition in the liver, which is not related with history of alcoholism. Besides hepatic steatosis, the pathological features of NAFLD could also include liver cell damage, mixed inflammatory cell infiltration and liver fibrosis. According to statistics, almost20%～25%of the U.S. citizens has NAFLD, while there is at least up to30%of the general population suffering from NAFLD in Europe. The prevalence rate of male Spanish suffering from this disease is up to45%-50%. The percentage of Chinese citizens who got this disease is about31%in cities and about12%in poverty-stricken areas. Based on above statistics, NAFLD has become a major threat to the health of people. Some studies have shown that NAFLD patients usually had one or more related metabolic disorders, such as central or overall obesity, type2diabetes mellitus (T2DM), atherosclerosis, hypertension and high cholesterol, which could exacerbate the severity of fatty liver. It is undeniable that there is no specific medicine for curing NAFLD in clinic, so finding effective medicine for curing NAFLD has attracted wide concern of medicine field.Exenatide is a kind of analogs of a glucagon like peptide-1(GLP-1) secreted by L cells in the gut, the drug is similar to GLP-1extracted from blunt trailing poisonous lizard saliva, and the homology with the molecular structure of GLP-1is53%, besides, there is high affinity between exenatide and GLP-1receptor in the body. At the same time, exenatide can also promote the secretion of insulin, generate glucagon suppression, stimulate islet B cells proliferation and differentiation, inhibit the apoptosis of B cells and so on. In addition, exenatide has the effect of lowering blood glucose, lipid metabolism, appetite control and reducing food absorption, but not cause hypoglycemia effect. So it can be safe for human, it provides a possibility for the treatment of NAFLD.In order to investigate the treatment effect and theory of exenatide on NAFLD and provide the theoretical foundation of therapeutic safety of exenatide on NAFLD, we have observed rat liver pathology, the percentage of liver weight in rats, liver function, total protein, blood lipid, the capacity of oxidization and antioxidation of serum and liver, insulin resistance index, and the expression of mRNA and protein of PPARa, ACOX1, SREBF-lc, ACCa and SCD1by establishing the model of NAFLD rat and taking polyene phosphatidylcholine as positive control group. The study found that, with increasing doses and time of exenatide used on rat, the percentage of rat liver weight, liver fat infiltration and liver inflammation reduced significantly, and liver fat particles reduced significantly or even disappeared; rat total protein, albumin, globulin, total bilirubin, direact and indirect bilirubin, liver function, lipid parameters and antioxidant capacity were improved significantly and directly, while exenatide significantly improved the expression of mRNA and protein of PPARa, SCD1and ACOX1, and reduced the expression of mRNA and protein of SREBF1and ACCa.The results of this study are showed below.1. rat model of NAFLD is established by high-fat diet, and12weeks later rat model of moderate fatty liver can be achieved.2. Rat model with NAFLDr treated by exenatide can show significantly the lower the fat content of the liver; this drug was been determined that regulate blood lipids and improve liver function.3.The first pathway to exenatide treatment of NAFLD may further improve the liver fatty acid β-oxidation by regulating expression of PPARa and ACOX1.4. The second pathway to exenatide treatment of NAFLD may further reduce mRNA and proteins expressions of SREBF-1and ACCa by reducing the exenatide and IR index, while promote mRNA expression of SCD1mRNA and its corresponding protein. By regulating above the three genes, exenatide can reduce further damage of NAFLD, and thereby protect the liver.5. Large doses of exenatide for injection can cause elevated levels of total bile acids in serum.