Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease

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 <i>Akkermansia muciniphila</i> (<i>A. muc</i>); however, whether it can alleviate ferroptosis remains unclear. The current study indicates <i>A. muc</i> 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-1<i>α</i> axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation <i>in vitro</i> and <i>in vivo</i>. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon <i>A. muc</i> 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 <i>A. muc</i> mediated antiferroptotic effects in the absence of other microbes. These data indicated that <i>A. muc</i> exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1<i>α</i> axis to alleviate ferroptosis <i>via</i> the inhibition of polyunsaturated fatty acid (PUFA) synthesis.