Consequences of reprogramming acetyl-CoA metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the mouse liver

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that induces the progression of steatosis to steatohepatitis with fibrosis in mice. Furthermore, TCDD reprograms hepatic metabolism by redirecting glycolytic intermediates while inhibiting lipid metabolism. Here, we examined the effect of TCDD on hepatic acetyl-coenzyme A (acetyl-CoA) and beta-hydroxybutyrate levels as well as protein acetylation and beta-hydroxybutyrylation. Acetyl-CoA is not only a central metabolite in multiple anabolic and catabolic pathways, but also a substrate used for posttranslational modification of proteins and a surrogate indicator of cellular energy status. Targeted metabolomic analysis revealed a dose-dependent decrease in hepatic acetyl-CoA levels coincident with the phosphorylation of pyruvate dehydrogenase (E1), and the induction of pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphatase, while repressing ATP citrate lyase and short-chain acyl-CoA synthetase gene expression. In addition, TCDD dose-dependently reduced the levels of hepatic beta-hydroxybutyrate and repressed ketone body biosynthesis gene expression. Moreover, levels of total hepatic protein acetylation and beta-hydroxybutyrylation were reduced. AMPK phosphorylation was induced consistent with acetyl-CoA serving as a cellular energy status surrogate, yet subsequent targets associated with re-establishing energy homeostasis were not activated. Collectively, TCDD reduced hepatic acetyl-CoA and beta-hydroxybutyrate levels eliciting starvation-like conditions despite normal levels of food intake.

Automated summary

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that induces liver damage and changes in hepatic metabolism. In this study, the effects of TCDD on hepatic acetyl-CoA and beta-hydroxybutyrate levels, as well as protein acetylation and beta-hydroxybutyrylation, were examined. The results showed that TCDD reduced hepatic acetyl-CoA and beta-hydroxybutyrate levels and decreased protein acetylation and beta-hydroxybutyrylation. These findings suggest that TCDD induces starvation-like conditions in the liver.