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.
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