Ah Receptor Anatomy: Implications for Dioxin Toxicity

毒素、致病性感染（病毒和细菌）和对肝脏的物理损伤导致肝组织损失，触发再生反应以恢复肝细胞质量。修复过程中的失调可能导致肝功能衰竭或肝癌。芳香烃 受体（AhR）是一种功能上与增殖过程相关的配体激活的转录因子。延长的AhR信号传导，如暴露于配体2，3，7，8-四氯二苯并-对-二恶英（TCDD）后发生的，诱导一系列毒性或适应性终点，包括组织损伤后肝再生失败。我们的长期目标是从机制上了解AhR如何通过调节细胞增殖来促进肝脏稳态，从而确定TCDD诱导的正常生物过程中断的分子基础。本申请中的中心假设指出，AhR诱导对氧磷酶1（PON 1）基因表达，以响应于 氧化低密度脂蛋白（oxLDL）在肝再生期间产生。该假设是基于几个观察。首先，一份报告说，PON 1-一种在高密度 负责抑制oxLDL产生的脂蛋白-是AhR靶基因。其次，最近发表的发现，剪切应力诱导的oxLDL的产生可以诱导AhR激活。第三，肝损伤引起的血流动力学变化导致oxLDL的形成。此外，基于我们的初步证据，我们提出PON 1的表达使用一个独特的AhR蛋白复合物结合到一个新的非共识异生素反应元件（NC-XRE）。本提案中所述的研究 将确定oxLDL诱导的PON 1表达是肝再生过程中NC-XRE介导的AhR依赖性过程，其中PON 1表达主要通过调节oxLDL形成来控制AhR活性。考虑到PON 1在预防心血管疾病中的作用， 现在被怀疑在肝脏内稳态中的作用，其通过AhR的调节直接将环境暴露问题与重要和普遍的人类健康问题联系起来。因此，对这些过程的机械理解是至关重要的。）

Toxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tissue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. Prolonged AhR signaling such as occurs following exposure to the ligand 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), induces a range of toxic or adaptive endpoints including a failure of liver regeneration following tissue injury. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify the molecular basis for TCDD-induced disruption of normal biological processes. The central hypothesis in this application states that the AhR induces paraoxonase 1 (PON1) gene expression in response to oxidized low-density lipoproteins (oxLDL) generated during periods of liver regeneration. The hypothesis is based on several observations. First, a report that PON1-an enzyme found in high-density lipoproteins responsible for inhibiting oxLDL production-is an AhR target gene. Second, the recently published finding that shear-stress induced production of oxLDL can induce AhR activation. Third, that hemodynamic changes triggered by liver injury lead to formation of oxLDL. Moreover, based on our preliminary evidence we propose that PON1 expression uses a unique AhR protein complex binding to a novel non-consensus xenobiotic response element (NC-XRE). The studies described in this proposal will establish that oxLDL- induced PON1 expression is a NC-XRE-mediated AhR-dependent process during liver regeneration, in which PON1 expression functions primarily to control AhR activity by regulating oxLDL formation. Given PON1's implicated role in protecting against cardiovascular disease, and now suspected role in liver homeostasis, its regulation by the AhR directly links environmental exposure concerns to significant and pervasive human health problems. Therefore, a mechanistic understanding of these processes is essential.)