The Effects Of SIRT1 Expression On Apoptosis Of Islet Beta-cell And Development Of Nonalcoholic Fatty Liver Disease In Rats

The acetylation/deacetylation regulation of proteins is one of important modes by which organism quickly regulates activity of zymoprotein. In vivo, many kinds of proteins and cell factors which can induce apoptosis of islet beta-cell in type 2 diabetes are controlled by this regulation. The mammalian Sir2 orthologue, SIRT1, as an NAD+ dependent deacetylase, deacetylates various substrates such as the p53 tumor suppressor, the FOXO transcription factors, the transcriptional coactivator PGC-1α, Ku70, NF-κB, TAFI68, P300, PCAF, and so on. It may be involved in apoptosis, cell cycle regulation, genetic transcription, substance metabolism and many other cellular and organismal regulatory pathways. The thesis mainly discusses the relationship between SIRT1 deacetylation and apoptosis of islet beta-cell in type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) induced by high fat feeding.In the rat models of high fat feeding and type 2 diabetes, the random blood sugar of rats with low dose streptozotocin (35mg/kg) injection increased significantly, but the fasting blood sugar was normal. On the base of chronic hyperglycemia, rats were fed with normal chow and high fat diet respectively to mimic glucotoxicity and lipotoxicity. As a result, hyperlipemia had no obvious impairment to beta-cell when glycemia was normal. The long-term chronic hyperglycemia, however, had independent impacts on function of islet beta-cell. Furthermore, chronic hyperglycemia dramaticly promoted function impairment of beta-cell by lipotoxicity. The finding shows that chronic hyperglycemia is necessary for lipotoxicity impairment to islet beta-cell, and lipotoxicity is dependent on glucotoxicity.The chronic hyperglycemia promoted dramaticly apoptosis of islet beta-cell when glucolipotoxicity impaired function of beta-cell. The mRNA and protein expression of SIRT1 in islet beta-cell reduced significantly. Lipotoxicity further increased apoptosis of beta-cell in the background of chronic hyperglycemia. The mRNA and protein expression of SIRT1 further decreased obviously. The glucotoxicity and lipotoxicity cooperated on apoptosis of islet beta-cell. Calorie restriction apparently raised the mRNA and protein expression of SIRT1 in beta-cell, and then lowered apoptosis ratio of islet beta-cell. These results indicate that depressed SIRT1 expression may be the one of important mechanisms by which prominently facilitates beta-cell apoptosis in type 2 diabetes.The histopathology of liver suggests that rats fed with high fat diet for three months developed typical NAFLD. In these high fat feeding rats, the SIRT1 expression of liver reduced significantly and the mitochondria displayed retrogression changes. After strict calorie restriction for one month, the SIRT1 expression of liver increased and the pathology changes of NAFLD was obviously improved, shows that the SIRT1 expression plays an important role in NAFLD induced by high fat feeding. Calorie restriction improves insulin resistance and mitochondrion malfunction by increased SIRT1 expression, and then ameliorates oxidative stress to treat NAFLD.Our findings make clear that the changes of SIRT1 expression take an important action in islet beta-cell apoptosis of type 2 diabetes and development and turnover of NAFLD. Reduced SIRT1 expression may be a general mechanism of various diseases. As expected, SIRT1 possibly becomes a new target in treatment of diabetes and NAFLD.