2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism.
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DOI：
10.1038/s41598-017-05656-8
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发表时间：
2017-07-19
影响因子：
4.6
通讯作者：
Zacharewski TR
中科院分区：
文献类型：
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作者：
Fader KA;Nault R;Zhang C;Kumagai K;Harkema JR;Zacharewski TR
2，3，7，8-四氯二苯并二恶英（TCDD）是一种持久性环境污染物，通过激活芳香烃受体（AhR）而引起肝毒性。雄性C57 BL/6小鼠经口灌胃TCDD（0.01-30 µg/kg），每4天一次，持续28天，出现胆管增生和胆管周围炎。质谱分析检测到总肝胆汁酸水平增加了4.6倍，尽管参与胆固醇和初级胆汁酸生物合成的基因（包括Cyp 7a 1）受到协调抑制。具体来说，TCDD引起牛磺石胆酸（TLCA）增加>200倍，TLCA是一种与胆管增殖相关的有效G蛋白偶联胆汁酸受体1（GPBAR 1）激动剂。微生物胆汁酸代谢位点（bsh、baiCD）水平升高与TLCA和其他次级胆汁酸蓄积一致。粪便胆汁酸降低2.8倍，表明由于回肠转运蛋白（Slc 10a 2，Slc 51 a）的诱导和全肠通过时间和肠通透性的增加，肠重吸收增强。此外，血清胆汁酸增加45.4倍，与血液-肝细胞转运蛋白抑制（Slco 1a 1、Slc 10a 1、Slco 2b 1、Slco 1b 2、Slco 1a 4）和肝细胞-血液转运蛋白诱导（Abcc 4、Abcc 3）一致。这些结果表明，肝肠循环的系统性改变，以及宿主和微生物群胆汁酸代谢，有利于胆汁酸积累，有助于AhR介导的肝毒性。
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.