Ah Receptor Anatomy: Implications for Dioxin Toxicity

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DESCRIPTION (provided by applicant): This is an application in response to the NIH Notice Number NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application." 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.) PUBLIC HEALTH RELEVANCE: Injury to the liver resulting in a loss of tissue triggers a repair process designed to restore liver mass, where inappropriate repair can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a protein that plays a central role in liver repair in addition to being a sensor for environmental pollutants. Therefore, the AhR directly links environmental exposure concerns to significant and pervasive human health problems.)