Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
19 08 2020
19 08 2020
Historique:
received:
26
07
2019
revised:
11
02
2020
accepted:
30
06
2020
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
24
6
2021
Statut:
ppublish
Résumé
Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.
Identifiants
pubmed: 32817366
pii: 12/557/eaay8798
doi: 10.1126/scitranslmed.aay8798
pmc: PMC7976849
mid: NIHMS1673160
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Acid Ceramidase
EC 3.5.1.23
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL123778
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK114548
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA097132
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242447
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118128
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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