Mitochondrial folate metabolism-mediated α-linolenic acid exhaustion masks liver fibrosis resolution.

ABSTRACT: Sustainable TGF-β1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-β1 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-β1 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-β1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in non

SUBMITTER: Gao Y 

PROVIDER: S-EPMC10344950 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature