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

Abstract

Abstract2,3,7,8-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 β-hydroxybutyrate levels as well as protein acetylation and β-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 β-hydroxybutyrate and repressed ketone body biosynthesis gene expression. Moreover, levels of total hepatic protein acetylation and β-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 β-hydroxybutyrate levels eliciting starvation-like conditions despite normal levels of food intake.

Transcriptomic analysis of the effect of shaking and tumbling degree on quality formation of Wuyi rock tea

“…Starch and sucrose metabolism converted macromolecular sugars into small molecules of glucose (Li et al., 2022). Glucose catabolism produces large amounts of intermediate metabolites such as pyruvate and acetyl coenzyme A (Cholico et al., 2023). Glycolysis/gluconeogenesis pathway in turn promotes the binding of pyruvate, acetyl coenzyme A, and so forth for the interconversion of sugars, lipids, and amino acids in vivo (Zhang, 2023).…”

Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice

“…3 A ), while NAGS requires acetyl-CoA. Previous studies report that TCDD elicits an energy crisis by disrupting available ATP stores ( 23 ) as well as acetyl-CoA stores ( 24 ). In total, Cps1 , Nags , Ass1 , Asl , Slc25a13 , and Slc25a15 exhibited putative DREs (pDREs) and AHR binding.…”

“…Alterations in branch chain amino acid levels relative to aromatic amino acids (Fischer’s ratio) are associated with compromised liver function ( 30 , 31 ), while elevated phenylalanine and tyrosine levels indicate advanced liver disease ( 32 ). Collectively, these changes suggest TCDD compromised liver function that likely contributed to hepatotoxicity over time despite modest increases in alanine transaminase and the absence of gross histopathological observations ( 10 , 24 ).…”

“…Previous studies have shown that persistent AHR activation by TCDD disrupts carbohydrate and lipid metabolism ( 11 , 12 , 33 ). This not only compromised bioenergetics but also altered intracellular messenger levels and disrupted metabolic programming, resulting in the accumulation of toxic intermediates ( 24 , 79 ). In this study, the effects on gene expression and amino acid metabolism associated with the urea cycle suggest that TCDD repressed the urea cycle, resulting in ammonia accumulation that further contributes to the toxicity burden of TCDD and related compounds due to persistent AHR activation.…”

“…Briefly, postnatal day 28 mice were orally gavaged with 100 μl of sesame oil or 0.03, 0.1, 0.3, 1, 3, 10, and 30 μg/kg TCDD every 4 days for 28 days. This dosing regimen, which has been used in previous studies ( 9 , 10 , 11 , 12 , 24 , 80 , 81 , 82 ), was used to approach TCDD levels comparable to reported human serum levels, following intentional poisoning, exposure due to industrial accidents, and accumulation due to background environmental exposures ( 10 ). On day 28 of the study, mice were euthanized via carbon dioxide overdose, after which blood was collected by cardiac puncture.…”