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Protein kinase STK25 aggravates the severity of non-alcoholic fatty pancreas disease in mice

Journal article
Authors Esther Nuñez Durán
Belén Chanclón
Silva Sütt
Joana Real
Hanns-Ulrich Marschall
Ingrid Wernstedt Asterholm
Emmelie Cansby
Margit Mahlapuu
Published in Journal of Endocrinology
Volume 234
Issue 1
Pages 15-27
ISSN 0022-0795
Publication year 2017
Published at Wallenberg Laboratory
Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 15-27
Language en
Links doi.org/10.1530/joe-17-0018
Keywords non-alcoholic fatty pancreas disease, ectopic lipid storage, beta-cell dysfunction, endoplasmic-reticulum stress, beta-cell apoptosis, insulin-resistance, metabolic syndrome, skeletal-muscle, tca cycle, dysfunction, liver, steatosis, defects, Endocrinology & Metabolism
Subject categories Clinical Medicine, Chemical Sciences

Abstract

Characterising the molecular networks that negatively regulate pancreatic beta-cell function is essential for understanding the underlying pathogenesis and developing new treatment strategies for type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic fat storage, meta-inflammation, and fibrosis in liver and skeletal muscle. Here, we assessed the role of STK25 in control of progression of non-alcoholic fatty pancreas disease in the context of chronic exposure to dietary lipids in mice. We found that overexpression of STK25 in high-fat-fed transgenic mice aggravated diet-induced lipid storage in the pancreas compared with that of wild-type controls, which was accompanied by exacerbated pancreatic inflammatory cell infiltration, stellate cell activation, fibrosis and apoptosis. Pancreas of Stk25 transgenic mice also displayed a marked decrease in islet beta/alpha-cell ratio and alteration in the islet architecture with an increased presence of a-cells within the islet core, whereas islet size remained similar between genotypes. After a continued challenge with a high-fat diet, lower levels of fasting plasma insulin and C-peptide, and higher levels of plasma leptin, were detected in Stk25 transgenic vs wild-type mice. Furthermore, the glucose-stimulated insulin secretion was impaired in high-fat-fed Stk25 transgenic mice during glucose tolerance test, in spite of higher net change in blood glucose concentrations compared with wild-type controls, suggesting islet beta-cell dysfunction. In summary, this study unravels a role for STK25 in determining the susceptibility to diet-induced nonalcoholic fatty pancreas disease in mice in connection to obesity. Our findings highlight STK25 as a potential drug target for metabolic disease.

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