Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver.
J Lipid Res
; 61(2): 178-191, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-31857389
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Proteínas Serina-Treonina Quinases
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Peroxissomos
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Peptídeos e Proteínas de Sinalização Intracelular
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Fígado Gorduroso
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Gotículas Lipídicas
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Lipid Res
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Suécia