Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice

Acyl-CoA oxidase 2 (Acox2) is an enzyme involved in peroxisomal bile acid synthesis and branched-chain fatty acid degradation. Acox2 knockout (-/-) mice spontaneously developed liver cancer with marked lymphocytic infiltrate. Tandem-affinity purification coupled with mass spectrometry analysis revea...

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Detalles Bibliográficos
Autores: Zhang, Yuan, Chen, Yuling, Zhang, Zhao, Tao, Xiang, Xu, Sha|||0000-0003-4685-6296, Zhang, Xinyan, Zurashvili, Tinatin, Lu, Zhouping, Bayascas Ramírez, José Ramón|||0000-0002-6096-2151, Jin, Liping|||0000-0002-2755-0489, Zhao, Jianyuan|||0000-0001-9861-0330, Zhou, Xiangyu|||0000-0003-2115-4175
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:258137
Acceso en línea:https://ddd.uab.cat/record/258137
https://dx.doi.org/urn:doi:10.1038/s41419-022-04725-9
Access Level:acceso abierto
Palabra clave:Metabolic disorders
Post-translational modifications
Descripción
Sumario:Acyl-CoA oxidase 2 (Acox2) is an enzyme involved in peroxisomal bile acid synthesis and branched-chain fatty acid degradation. Acox2 knockout (-/-) mice spontaneously developed liver cancer with marked lymphocytic infiltrate. Tandem-affinity purification coupled with mass spectrometry analysis revealed that Acox2 interacted with methylcrotonoyl-CoA carboxylase followed by co-immunoprecipitation confirmation. Here we reported that non-histone lysine crotonylation (Kcr) levels were downregulated in Acox2 -/- mice livers. Interestingly, Kcr signals were concentrated in the nucleus of tumor cells but mostly located in the cytoplasm of adjacent normal liver cells of Acox2 -/- mice. Quantitative analysis of the global crotonylome further revealed that 54% (27/50) of downregulated non-histone Kcr sites were located in mitochondrial (11/50) and peroxisomal (17/50) enzymes including Ehhadh, Scp2, Hsd17b4, Crot, Etfa, Cpt1a, Eci1/2, Hadha, Etfdh, and Idh2. Subsequent site-directed mutagenesis and transcriptome analysis revealed that Ehhadh K 572 cr might have site-specific regulatory roles by downregulating TOP3B expression that lead to increased DNA damage in vitro. Our findings suggested Acox2 is a regulator of Kcr that might play critical role on hepatic metabolic homeostasis.

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