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

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, Darren N. Saunders, Carina Sihlbom, Andrew J. Hoy, Margit Mahlapuu

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)178-191
Number of pages14
JournalJournal of lipid research
Volume61
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • nonalcoholic fatty liver disease
  • protein kinases
  • serine/threonine kinase 25
  • steatohepatitis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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