2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
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DOI：
10.1038/s41598-020-71795-0
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发表时间：
2020-09-09
影响因子：
4.6
通讯作者：
Zacharewski, Tim R.
中科院分区：
文献类型：
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作者：
Fling, Russell R.;Doskey, Claire M.;Zacharewski, Tim R.
2,3,7,8-四氯二苯并-对二恶英 (TCDD) 是一种持久性环境污染物，可诱发脂肪变性，并可进展为伴有纤维化的脂肪性肝炎，其病理学与非酒精性脂肪肝病 (NAFLD) 的发展阶段平行。巧合的是，一碳代谢 (OCM) 基因表达和代谢物在 NAFLD 进展过程中经常发生改变。在这项研究中，研究了 TCDD 对小鼠肝脏 OCM 的时间和剂量依赖性影响。尽管 AhR ChIP-seq 在 2 小时富集，但 OCM 基因表达在推注剂量 TCDD 后 72 小时内没有改变。重复治疗后 28 天时，蛋氨酸腺苷转移酶 1A (Mat1a)、腺苷高半胱氨酸酶 (Achy) 和甜菜碱高半胱氨酸 S-甲基转移酶 (Bhmt) mRNA 和蛋白质水平的剂量依赖性抑制比 8 天时更高。因此，甲硫氨酸、甜菜碱和同型半胱氨酸的水平呈剂量依赖性增加，而S-腺苷甲硫氨酸、S-腺苷高半胱氨酸和胱硫醚表现出非单调剂量依赖性反应，与 OCM 中间体的调节和甘氨酸 N-甲基转移酶 (Gnmt) 的抑制一致。然而，对 SAM 依赖性多胺和肌酸代谢的剂量依赖性影响不能直接归因于 SAM 水平的变化。总的来说，这些结果表明，在 TCDD 引起的脂肪变性发展为伴有纤维化的脂肪性肝炎的背景下，持续的 AhR 激活会在转录物、蛋白质和代谢物水平上扰乱肝脏 OCM 代谢。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis that can progress to steatohepatitis with fibrosis, pathologies that parallel stages in the development of non-alcoholic fatty liver disease (NAFLD). Coincidently, one carbon metabolism (OCM) gene expression and metabolites are often altered during NAFLD progression. In this study, the time- and dose-dependent effects of TCDD were examined on hepatic OCM in mice. Despite AhR ChIP-seq enrichment at 2 h, OCM gene expression was not changed within 72 h following a bolus dose of TCDD. Dose-dependent repression of methionine adenosyltransferase 1A (Mat1a), adenosylhomocysteinase (Achy) and betaine-homocysteine S-methyltransferase (Bhmt) mRNA and protein levels following repeated treatments were greater at 28 days compared to 8 days. Accordingly, levels of methionine, betaine, and homocysteic acid were dose-dependently increased, while S-adenosylmethionine, S-adenosylhomocysteine, and cystathionine exhibited non-monotonic dose-dependent responses consistent with regulation by OCM intermediates and repression of glycine N-methyltransferase (Gnmt). However, the dose-dependent effects on SAM-dependent metabolism of polyamines and creatine could not be directly attributed to alterations in SAM levels. Collectively, these results demonstrate persistent AhR activation disrupts hepatic OCM metabolism at the transcript, protein and metabolite levels within context of TCDD-elicited progression of steatosis to steatohepatitis with fibrosis.