Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease.
10.1016/j.apsb.2024.10.010
- Author:
Aoxiang ZHUGE
1
;
Shengjie LI
2
;
Shengyi HAN
2
;
Yin YUAN
2
;
Jian SHEN
2
;
Wenrui WU
2
;
Kaicen WANG
2
;
Jiafeng XIA
2
;
Qiangqiang WANG
2
;
Yifeng GU
2
;
Enguo CHEN
1
;
Lanjuan LI
2
Author Information
1. Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
- Publication Type:Journal Article
- Keywords:
Acetate;
Adenosine 5′-monophosphate-activated protein kinase;
Akkermansia muciniphila;
Ferroptosis;
Lipid peroxidation;
Metabolic-associated fatty liver disease;
Polyunsaturated fatty acid synthesis
- From:
Acta Pharmaceutica Sinica B
2025;15(1):151-167
- CountryChina
- Language:English
-
Abstract:
Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.
