Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity.
Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity.
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DOI：
10.1016/j.taap.2017.02.006
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发表时间：
2017-04-15
影响因子：
3.8
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;Kirby MP;Markous G;Matthews J;Zacharewski TR
持久性芳香烃受体(AhR)激动剂可诱导小鼠肝脏脂质堆积、氧化应激、炎症和纤维化，并呈剂量依赖性。铁(Fe)通过催化产生活性氧(ROS)来促进AhR介导的氧化应激。为进一步研究铁在AHR介导的肝毒性中的作用，用C57BL/6雄性小鼠灌胃芝麻油或0.01~30μg/kg的2，3，7，8-四氯二苯并-对二恶英，每4天一次，连续28天。十二指肠上皮和肝脏RNA-Seq数据与肝脏AhR芯片序列、毛细管电泳蛋白测定和临床化学分析相结合。TCDD剂量依赖地抑制肝脏铁稳态的主要调节因子海普西丁(HAMP和HAMP2)的表达，导致血清铁增加2.6倍，同时累积的铁溢出到尿中。在转铁蛋白饱和度不变的情况下，肝脏总铁水平可忽略不计地升高。此外，TCDD还诱导了血红素生物合成的基因表达的剂量依赖性变化，包括诱导氨基酮戊酸合成酶1(ALAS1)和抑制尿卟啉原脱羧酶(UROD)，导致肝脏氯化血红素增加50%，尿卟啉总量增加13.2倍。与这种血红素积累相一致的是，差异基因表达表明，血红素激活了BACH1和REV-ERBα/β，分别导致血红素加氧酶1(Hmox1)的诱导和脂肪酸生物合成的抑制。总而言之，这些结果表明，HAMP抑制、铁积累和增加的血红素水平共同促进了氧化应激和TCDD诱导的肝毒性的进展。
Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30 μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.