Translational Research of Secretogranin 3 in Metabolic Syndrome

Metabolic syndrome is highly correlated with diabetes, hyperlipidemia, and obesity; however, the important factors and the pathophysiological mechanisms that link these diseases are still obscure. In order to investigate these issues, we established a high fat diet-fed animal model that mimic human metabolic syndrome. Using microarray analysis, we found that the hepatic expression of secretogrnin 3 (SCG3) was significantly increased in mice fed with a high fat diet. It was known that the single nucleotide polymorphism of SCG3 is related to metabolic syndrome and diabetic retinopathy. With the support by Ministry of science and technology, although we found serum SCG3 concentration is significantly in subjects with metabolic syndrome, and related to fasting plasma glucose, waist circumference, and lipid profile, the causal relationship still needs further studies to clarify. In the first year of this project, we will investigate the role of SCG3 in the regulation of blood glucose. We found that serum SCG3 concentrations were elevated in patients with pr-diabetes, and diabetes. In addition, overexpression of SCG3 in hepatocytes increased the sorting of membrane insulin receptor into autophagosome, and further led to the development of insulin resistance. However, the application potential for the treatment of diabetes by SCG3 is still obscure. Therefore, we will use a lentiviral vector to overexpress SCG3 in the liver and evaluate the glucose regulation in experimental animals. In addition, we will specifically knockdown SCG3 expression in the liver by lenti-viral vector containing short hairpin RNA targeted to SCG3 to evaluate the therapeutic potential of SCG3 in diabetes. Moreover, it was known that SCG3 is related to cholesterol utility, and we found that serum SCG3 levels are positively related to serum cholesterol concentrations. However, the role of SCG3 in hypercholesterolemia is still unknown. Therefore, this project will also investigate the effect and relationship in hypercholesterolemia using a translational medicine manner. Finally, since we found that serum SCG3 concentration was positively associated with obesity and the expression of SCG3 was significantly increased in the epididymal adipose tissue, we will analyze the regulatory factors that related to the SCG3 expression, and investigate the role of SCG3 in adipocyte functions.