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Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Journal article
Authors Annika Nerstedt
Yeshwant Kurhe
Emmelie Cansby
Mara Caputo
Lei Gao
Egor Vorontsov
Marcus Ståhlman
Esther Nuñez Durán
Jan Borén
Hanns-Ulrich Marschall
Douglas G. Mashek
D. N. Saunders
Carina Sihlbom
A. J. Hoy
Margit Mahlapuu
Published in Journal of Lipid Research
Volume 61
Issue 2
Pages 178-191
ISSN 0022-2275
Publication year 2020
Published at Wallenberg Laboratory
Core Facilities, Proteomics
Institute of Biomedicine
Department of Chemistry and Molecular Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 178-191
Language en
Links dx.doi.org/10.1194/jlr.RA119000316
Keywords protein kinases, nonalcoholic fatty liver disease, steatohepatitis, serine, threonine kinase 25, acid-binding protein, chain fatty-acid, targeting signal-1, insulin-resistance, l-fabp, expression, reveals, glucose, mice, mitochondria, Biochemistry & Molecular Biology
Subject categories Molecular biology

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25(-/-) versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25's action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

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