Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty‐first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high‐fat diet‐induced systemic hyperglycemia and hyperinsulinemia, improved whole‐body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl‐coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single‐nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69–83)

Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

“…Furthermore, STK25 knockdown attenuates lipid accumulation in human hepatocytes and mouse liver by repressing lipid synthesis and enhancing b-oxidation and VLDL-TAG secretion, and the reciprocal phenotype is seen when STK25 protein is overexpressed (15-18, 21, 24). Similar to our findings in MST3-deficient human hepatocytes, our previous studies also reveal lower hepatic ACC levels in Stk25 knockout mice as well as in mice treated with Stk25 antisense oligonucleotides (15,21,24). Even though the localization and function of MST3 and STK25 in liver cells partly overlap and they share high sequence homology, the results of this study clearly show that the presence of STK25 in human hepatocytes cannot compensate for the loss of MST3 in control of lipid homeostasis.…”

“…Partial knockdown of MST3 has recently been shown to lower hyperglycemia and hyperinsulinaemia and to improve insulin sensitivity in mice fed a high-fat diet (13). Interestingly, our previous studies have revealed that depletion of the closely related Ste20-type kinase STK25 in mice also protects against high-fat diet-induced glucose intolerance and insulin resistance and reduces both ectopic lipid storage and meta-inflammation in peripheral tissues prone to diabetic damage; of note, we observed the reciprocal phenotype in obese mice that overexpress STK25 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

STK25 regulates oxidative capacity and metabolic efficiency in adipose tissue

“…We found that STK25-overexpressing transgenic mice display impaired whole-body glucose tolerance and insulin sensitivity compared with WT littermates when fed a high-fat diet (Cansby et al 2013). Reciprocally, our studies showed that repression of STK25 activity in mice by genetic depletion or antisense oligonucleotide (ASO) treatment protects against high-fat diet-induced glucose intolerance and insulin resistance (Amrutkar et al 2015a, Nunez-Duran et al 2018. Furthermore, we observed a markedly accelerated ectopic lipid accumulation, combined with aggravated inflammatory infiltration and fibrosis, in the liver, skeletal muscle and pancreas of high-fat-fed Stk25 transgenic mice compared with WT littermates (Amrutkar et al 2015b, Chursa et al 2017.…”

“…STK25 is broadly expressed, with high mRNA and protein levels detected both in brown and white adipose tissues (BAT and WAT (Nerstedt et al 2012, Cansby et al 2013, Amrutkar et al 2015a); however, the physiological function of STK25 in adipocytes remains elusive. On the basis of our previous findings, which reveal a central role of STK25 in control of lipid accumulation, chronic lowgrade inflammation and fibrosis in key metabolic organs liver, skeletal muscle and pancreas of high-fat-fed mice (Nerstedt et al 2012, Cansby et al 2013, Amrutkar et al 2015a,b, 2016a,b, Chursa et al 2017, 2018, we hypothesized that STK25 is also involved in the regulation of adipose tissue dysfunction in connection to obesity. Here, we provide the first evidence for key cell-specific role of STK25 in controlling the mitochondrial function and metabolic balance of lipid utilization vs lipid storage in the BAT and WAT of obese mice, suggesting that STK25 repression offers a strategy for establishing healthier adipose tissue in the context of chronic exposure to dietary lipids.…”

“…In the search for novel targets that regulate wholebody energy metabolism in the context of nutritional stress and obesity, we recently described serine/threonine protein kinase (STK)25, a member of the sterile 20 (STE20) kinase superfamily (Thompson & Sahai 2015), as a critical regulator of lipid partitioning and systemic glucose and insulin homeostasis (Nerstedt et al 2012, Cansby et al 2013, Amrutkar et al 2015a,b,2016a,b, Chursa et al 2017, 2018. We found that STK25-overexpressing transgenic mice display impaired whole-body glucose tolerance and insulin sensitivity compared with WT littermates when fed a high-fat diet (Cansby et al 2013).…”