STK25 as a regulator of lipid accumulation

Type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), have become widespread metabolic disorders that have reached epidemic proportions. Obesity, with ectopic lipid accumulation, is the main factor for the development and subsequent progression of T2DM and NASH. To develop effective pharmacological treatment strategies against these metabolic diseases, it is important to understand molecular mechanisms that control ectopic lipid deposition and insulin resistance. Previous findings demonstrate that inhibition of serine/threonine protein kinase (STK25) leads to protection against HFD-induced liver steatosis and improved whole- body glucose tolerance and insulin sensitivity. In contrast, STK25 overexpression results in aggravated steatosis, promoting NAFLD and driving NASH development. Based on these studies, we investigated STK25 in the development of diet-induced NASH, described in Paper I. In this project, we found that mice fed methionine- choline deficient (MCD) diet were protected against NASH development following depletion of STK25. However, STK25 overexpression led to development of a more severe NASH phenotype when mice were challenged with MCD diet. In Paper II, we found that overexpression of STK25 leads to increased ectopic lipid storage, fibrosis and inflammation in skeletal muscle of mice fed high-fat diet (HFD). Moreover, STK25-overexpressing mice had decreased in vivo insulin-stimulated glucose uptake, decreased endurance exercise performance and impairments in β-oxidation. We also explored the role of STK25 in adipocyte lipid accumulation and maturation in Paper III using 3T3-L1 preadipocyte cells. We found that 3T3-L1 cells accumulated less lipid droplets and had several markers of adipocyte maturation reduced when STK25 was silenced prior to differentiation. Furthermore, we show a significant positive correlation between adipogenesis markers and STK25 expression in human adipose tissue. Taken together, work in this thesis contributes to the concept that STK25 is a potential drug target for prevention and/or treatment of obesity-associated T2DM, NAFLD and NASH

Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model

Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(−/−) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(−/−) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes