Mitochondrial folate metabolism-mediated α-linolenic acid exhaustion masks liver fibrosis resolution.
J Biol Chem
; 299(7): 104909, 2023 07.
Article
en En
| MEDLINE
| ID: mdl-37307917
ABSTRACT
Sustainable TGF-ß1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-ß1 signaling remains unclear. In this study, we revealed that dietary folate restriction promoted the resolution of liver fibrosis in mice with nonalcoholic steatohepatitis. In activated hepatic stellate cells, folate shifted toward mitochondrial metabolism to sustain TGF-ß1 signaling. Mechanistically, nontargeted metabolomics screening identified that α-linolenic acid (ALA) is exhausted by mitochondrial folate metabolism in activated hepatic stellate cells. Knocking down serine hydroxymethyltransferase 2 increases the bioconversion of ALA to docosahexaenoic acid, which inhibits TGF-ß1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in nonalcoholic steatohepatitis mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/TGF-ßR1 reproduction is a feedforward signaling to sustain profibrotic TGF-ß1 signaling, and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácido alfa-Linolénico
/
Ácido Fólico
/
Cirrosis Hepática
/
Mitocondrias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2023
Tipo del documento:
Article
País de afiliación:
China