Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis.
NASH
autophagy
high-fat diet
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
25
11
2018
revised:
30
04
2019
accepted:
03
05
2019
entrez:
10
10
2019
pubmed:
9
10
2019
medline:
17
4
2020
Statut:
ppublish
Résumé
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild-type mice. In line, liver-specific ASK1 overexpression protected mice from the development of high-fat diet-induced hepatic steatosis and carbon tetrachloride-induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.
Identifiants
pubmed: 31595673
doi: 10.15252/emmm.201810124
pmc: PMC6783644
doi:
Substances chimiques
MAP Kinase Kinase Kinase 5
EC 2.7.11.25
MAP3K5 protein, human
EC 2.7.11.25
Map3k5 protein, mouse
EC 2.7.11.25
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10124Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : 310030-160129
Pays : International
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : 310030-179344
Pays : International
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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