Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01–30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.
Highlights
Metabolic syndrome (MetS) is defined as a collection of cardiometabolic factors including obesity, dyslipidemia, hypertension, and hyperglycemia which increase the risk of developing cardiovascular disease, type II diabetes, and hepatocellular carcinoma[1]
TCDD increased levels of hepatic taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation and cholestasis[28, 29]
The histopathological features associated with TCDD-elicited hepatotoxicity in both female and male C57BL/6 mice orally gavaged with TCDD every 4d for 28d were compared
Summary
Metabolic syndrome (MetS) is defined as a collection of cardiometabolic factors including obesity, dyslipidemia, hypertension, and hyperglycemia which increase the risk of developing cardiovascular disease, type II diabetes, and hepatocellular carcinoma[1]. Specific bile acid species are endogenous ligands for a number of receptors including farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1), pregnane X receptor (PXR), vitamin D receptor (VDR), liver X receptor α (LXRα), and sphingosine-1-phosphate receptor 2 (S1P2)[18, 19]. They serve as important signaling molecules that regulate bile and cholesterol homeostasis, and glucose and energy metabolism. The qualitative and quantitative changes in bile acid homeostasis are consistent with alterations in host and intestinal microbiota metabolism, yielding hepatotoxic species that contribute to the development of steatohepatitis with fibrosis
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