Metabolic Regulation by the Nuclear Receptor CAR

描述(由申请人提供)：核激素受体CAR(NR1I3)介导药物代谢增加，以响应不同的外源物质。这些包括众所周知的诱导剂苯巴比妥(PB)，其功能是间接CAR激活剂，以及一些物种特异性激动剂或反向激动剂配体。我们发现，CAR还对升高的内源性有毒代谢物水平产生保护性反应。已发表的报告和我们的初步结果都表明，CAR的激活可以改变糖和脂代谢，并表明糖尿病和其他疾病的代谢失调会影响药物代谢。这些结果扩展了CAR的生理功能，远远超出了药物代谢的范围，并提出了有关其对基本代谢途径的影响的重要问题。此外，我们还表明，CAR激活直接诱导肝细胞生长和DNA复制，并阻断细胞凋亡。在短期内，这是一种保护肝脏的适应性反应，但慢性激活CAR会诱发肝脏肿瘤，从而引发关于这种异种受体在肝癌发生中的作用的关键问题。这个项目持续的长期目标是了解CAR的具体监管功能。目前的建议提出了两个具体的假设：1.CAR既是基本代谢途径的调节器，也是代谢失调的病理后果的靶点。2.CAR既是肝癌发生的早期调控因子，也是肝癌发生后期的治疗靶点。主要的两个具体目标是：1.明确CAR对基本代谢途径和靶基因的影响，并表征这些途径的失调对CAR介导的异种反应的影响。2.研究CAR在肝癌发生早期的作用，检测CAR反向激动剂在抑制肝癌生长中的作用，以及CAR与视网膜母细胞瘤基因产物和p-连环蛋白的功能相互作用。这些研究可以为代谢性疾病，特别是I型糖尿病的药物代谢变化提供新的见解，并为干预2型糖尿病和肝癌提供新的治疗途径，从而对人类健康产生具体和直接的影响。

DESCRIPTION (provided by applicant): The nuclear hormone receptor CAR (NR1I3) mediates increased drug metabolism in response to diverse xenobiotics. These include the well known inducer phenobarbital (PB), which functions as an indirect CAR activator, and a number of species-specific agonist or inverse agonist ligands. We have found that CAR also directs a protective response to elevated levels of endogenous toxic metabolites. Both published reports and our preliminary results demonstrate that CAR activation can alter glucose and lipid metabolism, and indicate that metabolic dysregulation in diabetes and other disorders affects drug metabolism. These results expand the physiologic functions of CAR well beyond drug metabolism and raise important questions regarding its impact on basic metabolic pathways. Moreover, we have also shown that CAR activation directly induces hepatocyte growth and DNA replication and blocks apoptosis. In the short term this is an adaptive response that protects the liver, but chronic CAR activation induces liver tumors, raising key issues regarding the role of this xenobiotic receptor in hepatocarcinogenesis. The continuing long term goal of this project is to understand the specific regulatory functions of CAR. The current proposal addresses two specific hypotheses: 1. CAR is both a modulator of basic metabolic pathways and a target of the pathologic consequences of metabolic dysregulation. 2. CAR is both a modulator of early stages of hepatocarcinogenesis and a therapeutic target in the later stages of this process. The two broad specific aims are to: 1. Define the impact of CAR on basic metabolic pathways and target genes, and characterize the effects of the dysregulation of such pathways on the xenobiotic responses mediated by CAR. 2. Characterize the role of CAR in the early stages of hepatocarcinogenesis, test the therapeutic potential of CAR inverse agonists in inhibition of liver tumor growth, and examine the functional interaction of CAR with the Retinoblastoma gene product and p-catenin. These studies could have specific and direct impact on human health by providing new insights into alterations in drug metabolism in metabolic disease, particularly Type I diabetes, and a new therapeutic avenues to intervene in both Type 2 diabetes and liver cancer.