期刊
FASEB JOURNAL
卷 30, 期 10, 页码 3628-3643出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201600562R
关键词
NAFLD; NASH; oxidative stress; inflammation; liver fibrosis
资金
- Swedish Research Council
- European Foundation for the Study of Diabetes/Lilly Research
- Novo Nordisk Foundation
- Swedish Heart and Lung Foundation
- Diabetes Wellness Network Sweden
- Swedish Diabetes Foundation
- P. and A. Hedlunds Foundation
- A. Wiberg Foundation
- Adlerbert Research Foundation
- I. Hultman Foundation
- S. and E. Goljes Foundation
- West Sweden Medical Training and Research Agreement (Avtal om Lakarutbildning och Forskning
- ALF) Program
- F. Neubergh Foundation
- Estonian Science Foundation
- European Foundation for the Study of Diabetes/Novo Nordisk research grant
- European Foundation for the Study of Diabetes [NN 2016_2] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0015842, NNF16OC0020802] Funding Source: researchfish
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) with a high risk of cirrhosis, liver failure, and hepatocellular carcinoma. Despite its high medical importance, the molecular mechanisms controlling progression from simple liver steatosis to NASH remain elusive. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid deposition, systemic glucose, and insulin homeostasis. To elucidate the role of STK25 in the development of NASH, we challenged Stk25-knockout and transgenic mice with a methionine and choline-deficient (MCD) diet. We show that Stk25(-/-) mice are protected against MCD-diet-induced NASH, as evidenced by repressed liver steatosis, oxidative damage, inflammation, and fibrosis, whereas Stk25 transgenic mice developed a more severe NASH phenotype, compared with corresponding wild-type littermates. Consistently, NASH features were suppressed in STK25-deficient human hepatocytes cultured in MCD medium, and reciprocally enhanced in STK25-overexpressing cells. We also found a significant positive correlation in human liver biopsies between STK25 expression and NASH development. The study provides evidence for multiple roles of STK25 in NASH pathogenesis and future investigations to address the potential therapeutic relevance of pharmacological STK25 inhibitors in prevention and treatment of NASH are warranted.
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