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.
Bibliographical noteFunding Information:
This work was supported by grants from the Swedish Research Council, the European Foundation for the Study of Diabetes/Novo Nordisk Programme for Diabetes Research in Europe, the West Sweden Avtal om Läkarutbildning och Forskning (ALF) Program, the Novo Nordisk Foundation, the Swedish Heart-Lung Foundation, the Torsten Söder-bergs Foundation, the Swedish Diabetes Foundation, the Royal Society of Arts and Sciences in Gothenburg, the Åke Wiberg Foundation, the Adlerbert Research Foundation, the I. Hultman Foundation, the S. and E. Goljes Foundation, the F. Neubergh Foundation, the Prof. N. Svartz Foundation, the L. and J. Grönberg Foundation, the W. and M. Lundgren Foundation, and the I-B. and A. Lundbergs Research Foundation. A.J.H. is supported by a University of Sydney Robinson Fellowship. The authors declare that they have no conflicts of interest with the contents of this article. Manuscript received 6 August 2019 and in revised form 5 November 2019. Published, JLR Papers in Press, December 19, 2019 DOI https://doi.org/10.1194/jlr.RA119000316
© 2020 Nerstedt et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
- Nonalcoholic fatty liver disease
- Protein kinases
- Serine/threonine kinase 25