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

Area of Science:

• Biochemistry
• Toxicology
• Metabolomics

Background:

• 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant known to cause diverse toxic effects.
• TCDD's impact on intermediate metabolism, particularly via the aryl hydrocarbon receptor, is not fully understood.
• Understanding TCDD's specific metabolic reprogramming is crucial for assessing its toxicity.

Purpose of the Study:

• To elucidate the specific metabolic reprogramming effects of TCDD exposure in the liver.
• To identify key metabolites and pathways affected by TCDD.
• To investigate the mechanism underlying TCDD-induced hepatotoxicity.

Main Methods:

• Targeted liquid chromatography-mass spectrometry (LC-MS) analysis of hepatic extracts from TCDD-gavaged mice.
• Quantification of key metabolites including S-(2-carboxyethyl)-L-cysteine and itaconate.
• Analysis of gene expression related to cobalamin (Cbl) metabolism and methylmalonyl-CoA mutase (MUT) activity.

Main Results:

• TCDD exposure increased S-(2-carboxyethyl)-L-cysteine, an indicator of the Cbl-independent propionyl-CoA metabolism.
• TCDD inhibited methylmalonyl-CoA mutase (MUT) activity and decreased serum Cbl and hepatic cobalt levels.
• TCDD induced aconitate decarboxylase 1 (Acod1) and increased hepatic itaconate levels, suggesting a mechanism for MUT inhibition via itaconyl-CoA formation.

Conclusions:

• TCDD-induced Cbl depletion inhibits MUT activity, redirecting propionyl-CoA metabolism.
• The accumulation of acrylyl-CoA from this metabolic shift likely contributes to TCDD-induced hepatotoxicity.
• TCDD promotes steatosis to steatohepatitis with fibrosis through altered Cbl metabolism and subsequent liver injury.