title: STK25 is a critical determinant in nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) with a high risk of cirrhosis, liver failure, and hepatocellular carcinoma. Despite its high medical importance, the molecular mechanisms controlling progression from simple liver steatosis to NASH remain elusive. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid deposition, systemic glucose, and insulin homeostasis. To elucidate the role of STK25 in the development of NASH, we challenged Stk25-knockout and transgenic mice with a methionine and choline-deficient (MCD) diet. We show that Stk25-/-mice are protected against MCD-diet-induced NASH, as evidenced by repressed liver steatosis, oxidative damage, inflammation, and fibrosis, whereas Stk25 transgenic mice developed a more severe NASH phenotype, compared with corresponding wild-type littermates. Consistently, NASH features were suppressed in STK25-deficient human hepatocytes cultured in MCD medium, and reciprocally enhanced in STK25-overexpressing cells. We also found a significant positive correlation in human liver biopsies between STK25 expression and NASH development. The study provides evidence for multiple roles of STK25 in NASH pathogenesis and future investigations to address the potential therapeutic relevance of pharmacological STK25 inhibitors in prevention and treatment of NASH are warranted.-Amrutkar, M., Chursa, U., Kern, M., Nuñez-Durán, E., Ståhlman, M., Sütt, S., Borén, J., Johansson, B. R., Marschall, H.-U., Blüher, M., Mahlapuu, M. STK25 is a critical determinant in nonalcoholic steatohepatitis.
authors.affiliation: Lundberg Laboratory for Diabetes Research and.
authors.forename: Manoj
authors.initials: M
authors.lastname: Amrutkar
authors.affiliation: Lundberg Laboratory for Diabetes Research and.
authors.forename: Urszula
authors.initials: U
authors.lastname: Chursa
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kern
authors.affiliation: Lundberg Laboratory for Diabetes Research and.
authors.forename: Esther
authors.initials: E
authors.lastname: Nuñez-Durán
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Lundberg Laboratory for Diabetes Research and.
authors.forename: Silva
authors.initials: S
authors.lastname: Sütt
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, and.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Institute of Biomedicine, Electron Microscopy Unit, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bengt R
authors.initials: BR
authors.lastname: Johansson
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, and.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Lundberg Laboratory for Diabetes Research and margit.mahlapuu@gu.se.
authors.forename: Margit
authors.initials: M
authors.lastname: Mahlapuu
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D014280:Triglycerides; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases
keywords: NAFLD; NASH; inflammation; liver fibrosis; oxidative stress