Dioxin-elicited decrease in cobalamin redirects propionyl-CoA metabolism to the β-oxidation-like pathway resulting in acrylyl-CoA conjugate buildup.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Acyl Coenzyme A*/metabolism ; Environmental Pollutants*/toxicity ; Fatty Liver*/chemically induced ; Fatty Liver*/metabolism ; Liver*/drug effects ; Liver*/metabolism ; Polychlorinated Dibenzodioxins*/toxicity ; Vitamin B 12*/metabolism ; Vitamin B 12 Deficiency*/chemically induced ; Vitamin B 12 Deficiency*/complications; Aconitic Acid/metabolism ; Animals ; Cobalt/metabolism ; Cysteine/metabolism ; Humans ; Methylmalonyl-CoA Mutase/genetics ; Methylmalonyl-CoA Mutase/metabolism ; Mice ; Receptors, Aryl Hydrocarbon/metabolism ; Succinates/metabolism
    • Abstract:
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that induces diverse biological and toxic effects, including reprogramming intermediate metabolism, mediated by the aryl hydrocarbon receptor. However, the specific reprogramming effects of TCDD are unclear. Here, we performed targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD. We detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate from the spontaneous reaction between the cysteine sulfhydryl group and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β-oxidation-like metabolism of propionyl-CoA. TCDD repressed genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β-oxidation-like pathways as well as inhibited methylmalonyl-CoA mutase (MUT) at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or derivatization to 5'-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. Additionally, TCDD induced the gene encoding aconitate decarboxylase 1 (Acod1), the enzyme responsible for decarboxylation of cis-aconitate to itaconate, and dose-dependently increased itaconate levels in hepatic extracts. Our results indicate MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that forms an adduct with adenosylcobalamin. This adduct in turn inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment, which redirects propionyl-CoA metabolism to the alternate Cbl-independent β-oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multihit progression of steatosis to steatohepatitis with fibrosis.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Grant Information:
      P42 ES004911 United States ES NIEHS NIH HHS; R01 ES029541 United States ES NIEHS NIH HHS; R01 ES033898 United States ES NIEHS NIH HHS; T32 ES007255 United States ES NIEHS NIH HHS
    • Contributed Indexing:
      Keywords: acrylyl-CoA; dioxin; gene expression; liver; metabolism; mouse
    • Accession Number:
      0 (Acyl Coenzyme A)
      0 (Environmental Pollutants)
      0 (Polychlorinated Dibenzodioxins)
      0 (Receptors, Aryl Hydrocarbon)
      0 (Succinates)
      317-66-8 (propionyl-coenzyme A)
      3G0H8C9362 (Cobalt)
      5776-58-9 (acryloyl-coenzyme A)
      93371T1BXP (Aconitic Acid)
      EC 5.4.99.2 (Methylmalonyl-CoA Mutase)
      K848JZ4886 (Cysteine)
      P6YC3EG204 (Vitamin B 12)
      Q4516562YH (itaconic acid)
    • Publication Date:
      Date Created: 20220805 Date Completed: 20220929 Latest Revision: 20230214
    • Publication Date:
      20240829
    • Accession Number:
      PMC9418907
    • Accession Number:
      10.1016/j.jbc.2022.102301
    • Accession Number:
      35931118