Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Abstract

2,3,7,8 –Tetrachlorodibenzo –p –dioxin (TCDD) is a persistent environmental contaminant and the prototypical ligand for the aryl hydrocarbon receptor (AhR). AhR mediates the effects of TCDD and related compounds, including the reprograming of intermediate metabolism. Untargeted metabolomics analysis of hepatic extracts prepared from mice orally gavaged with TCDD every 4 days for 28 days identified the dose –dependent induction of acrylyl –CoA, a highly reactive toxic intermediate produced during the metabolism of propionyl –CoA in the cobalamin (Cbl) –independent β –oxidation –like pathway. Acrylyl –CoA is a biomarker of inborn errors of metabolism associated with propionic and methylmalonic acidemia associated with Cbl deficiency, transport and/or defects in Cbl –dependent methylmalonyl –CoA mutase (MUT). Although TCDD repressed gene expression for both the canonical Cbl –dependent carboxylase and the alternate Cbl –independent β –oxidation –like pathways, inhibition occurred only at 30 μg/kg TCDD while acrylyl –CoA levels increased at ~3 μg/kg. In contrast, TCDD decreased serum Cbl and hepatic cobalt levels at ~3 μg/kg TCDD consistent with the dose –dependent increase in acrylyl –CoA levels. TCDD elicited negligible effects on the expression of genes associated with Cbl absorption, transport, trafficking and derivatization to 5 –deoxy –adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition, TCDD induced the decarboxylation of cis –aconitate to itaconate by Acod1. Itaconate can then be activated to itaconyl –CoA, a MUT suicide inactivator that forms an adduct with AdoCbl, blocking MUT activity and reducing Cbl levels. Collectively, these results suggest MUT activity was impaired due to Cbl depletion by TCDD causing propionyl –CoA metabolism to be redirected to the alternate Cbl –independent β –oxidation –like pathway resulting in hepatic acrylyl –CoA accumulation.

Genome-Wide ChIPseq Analysis of AhR, COUP-TF, and HNF4 Enrichment in TCDD-Treated Mouse Liver

“…The present study examined the effect of TCDD on AhR, HNF4α and COUP-TFII genomic binding with subsequent effects on the expression of genes associated with liver function and hepatocyte differentiation. As a potent AhR agonist, TCDD dysregulates a plethora of hepatic functions in rodents, including lipoprotein assembly and export metabolism [17,19], bile acid homeostasis [14,30], cholesterol metabolism [17,19], lipid metabolism [13,17,19], glucose metabolism [25,26,31], iron and heme homeostasis [32], one-carbon metabolism [33], and cobalamin-dependent reactions [34]. Previous studies have established that the activated AhR can bind to DNA motif as a heterodimer with ARNT and associated with other transcription factors such as COUP-TF, HIF, HNF4, LRH1, NRF1, PPAR, and RXR [3].…”

Genome-wide ChIPseq analysis of AhR, COUP-TF, and HNF4 enrichment in TCDD-treated mouse liver

“…The present study examined the effect of TCDD on AhR, HNF4α and COUP-TFII genomic binding with subsequent effects on the expression of genes associated with liver function and hepatocyte differentiation. As a potent AhR agonist, TCDD dysregulates a plethora of hepatic functions in rodents including lipoprotein assembly and export metabolism (Angrish et al, 2013;Nault et al, 2017b), bile acid homeostasis (Fader et al, 2017b;Forgacs et al, 2012), cholesterol metabolism (Angrish et al, 2013;Nault et al, 2017b), lipid metabolism (Angrish et al, 2013;Cholico et al, 2021;Nault et al, 2017b), glucose metabolism (Fader et al, 2019;Nault et al, 2016aNault et al, , 2016b, iron and heme homeostasis (Fader et al, 2017a), one-carbon metabolism (Fling et al, 2020), and cobalamin-dependent reactions (Orlowska et al, 2021). Previous studies have established that the activated AhR can bind to DNA motif as a heterodimer with ARNT and associated with other transcription factors such as COUP-TF, HIF, HNF4, LRH1, NRF1, PPAR, and RXR (Dere et al, 2011).…”