title: Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole-body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high-fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild-type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild-type livers. Transgenic livers displayed reduced β-oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet-coating protein adipose differentiation-related protein, the level of which was increased 3.8 ± 0.7-fold in transgenic livers (P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet-associated protein that promotes NAFLD through control of lipid release from the droplets for β-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Manoj
authors.initials: M
authors.lastname: Amrutkar
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Emmelie
authors.initials: E
authors.lastname: Cansby
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Esther
authors.initials: E
authors.lastname: Nuñez-Durán
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pirazzi
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Stenfeldt
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: *Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, and Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden margit.mahlapuu@gu.se.
authors.forename: Margit
authors.initials: M
authors.lastname: Mahlapuu
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008079:Lipoproteins, VLDL; D017346:Protein Serine-Threonine Kinases; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases
keywords: NAFLD; lipid droplets; lipid metabolism; liver inflammation; steatohepatitis