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

Abstract

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.

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

“…Conversely, we found that siRNA knockdown of STK25 in IHHs and HepG2 cells attenuated lipid accumulation by stimulating β-oxidation and TAG secretion and inhibiting TAG synthesis. Consistent with these results, we observed augmented hepatic β-oxidation and VLDL-TAG export in Stk25-knockout mice fed a high-fat diet, extending the results from our earlier studies showing that Stk25 −/− mice are protected against dietinduced liver steatosis [7]. Moreover, we found a statistically significant positive association between STK25 mRNA expression and fat content in human liver.…”

“…Knockdown of STK25 reduces lipid deposition in IHHs and HepG2 cells via increased β-oxidation and TAG secretion combined with repressed lipid synthesis Our recent studies demonstrate that mice with genetic disruption of STK25 are protected from diet-induced liver steatosis [7]. To investigate the impact of STK25 knockdown on lipid metabolism in human hepatocytes, we transfected IHHs and HepG2 cells with STK25-specific siRNA or with a non-targeting control (NTC) siRNA.…”

“…Ectopic lipid storage in the liver is known to contribute to the pathogenesis of insulin resistance and type 2 diabetes [1,2]. We previously showed impaired systemic glucose and insulin homeostasis in Stk25 transgenic mice fed a high-fat diet [5] and the reciprocal phenotype in Stk25 −/− mice [7]. Consistent with these earlier findings, we observed that the effect of insulin on glucose uptake and production was lost in STK25-overexpressing human hepatocytes and significantly enhanced in STK25-deficient hepatocytes challenged by OA, which is consistent with the changes in lipid deposition pattern in these cells.…”

“…We found that partial knockdown of STK25 in the rat myoblast cell line L6 by small interfering (si)RNA improves insulin-stimulated glucose uptake [4]. Furthermore, genetic disruption of STK25 in knockout mice provides protection from the detrimental metabolic consequences of high-fat-diet exposure on liver and skeletal muscle lipid accumulation, accompanied by better preserved systemic glucose tolerance, reduced hepatic glucose production and increased whole-body insulin sensitivity [7]. These findings are reciprocal to the metabolic phenotype of high-fatfed transgenic mice overexpressing STK25, which develop marked liver steatosis combined with hyperinsulinaemia, impaired systemic glucose tolerance and insulin resistance compared with wild-type littermates [5,6].…”

“…In the search for novel targets that contribute to the pathogenesis of type 2 diabetes, we identified serine/threonine protein kinase 25 (STK25 [also referred to as YSK1 or SOK1]), a member of the sterile 20 (STE20) kinase superfamily [3], as a critical regulator of ectopic lipid deposition, systemic glucose and insulin homeostasis [4][5][6][7]. We found that partial knockdown of STK25 in the rat myoblast cell line L6 by small interfering (si)RNA improves insulin-stimulated glucose uptake [4].…”