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

被引:13
作者
Gao, Yanjie [1 ]
Zheng, Bingfeng [1 ]
Xu, Shuaiqi [1 ]
Zhao, Zhibo [1 ]
Liu, Wanyue [1 ]
Wang, Tingyu [1 ]
Yuan, Manman [1 ]
Sun, Xueqing [1 ]
Tan, Yang [1 ]
Xu, Qiang [1 ]
Wu, Xingxin [1 ]
机构
[1] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing, Jiangsu, Peoples R China
关键词
HEPATIC STELLATE CELLS; NEURAL-TUBE DEFECTS; FOLIC-ACID; TGF-BETA; FATTY-ACIDS; MECHANISMS; ACTIVATION; SUPPLEMENTATION; PHENOTYPE; INSIGHTS;
D O I
10.1016/j.jbc.2023.104909
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sustainable TGF-111 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-111 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-111 signaling. Mechanistically, nontargeted metabolomics screening identified that a-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-111 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in nonalcoholic steatohepatitis mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/ TGF-11R1 reproduction is a feedforward signaling to sustain profibrotic TGF-111 signaling, and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.
引用
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页数:15
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