The constitutive androstane receptor (CAR, NR1I3) is a member of the nuclear receptor superfamily that is expressed primarily in the liver. CAR plays a key role in regulating all three phases of biotransformation, pathways that determine the fates of metabolism and toxicity associated with exposures to drugs, other xenobiotics, and endogenous substances such as bile acids, thyroid hormone, heme, and steroids. Due to the importance of this receptor system as a determinant of xenobiotic disposition in man, together with CAR's increasingly recognized role as a physiological regulator, it is imperative to fully characterize the biological processes directed by the human CAR proteome. Progress in the previous research program included the discovery of novel forms of CAR, CAR2 and CAR3;receptors generated through the use of alternative splicing mechanisms that result in the insertion of 4- and 5- amino acids, respectively, within the receptors'ligand binding domain. These receptors are expressed simultaneously with CAR in human livers, but possess highly unique functional attributes. Unlike CAR itself, the variant CARs are ligand-activated receptors, exhibit selective chemical activation profiles, and appear to differentially modulate target gene expression. We hypothesize that alternative splicing enhances the functional diversity of CAR molecules, resulting in overlapping, yet discriminating roles as xenobiotic sensors, driving the interplay of hepatic gene expression networks that in turn, provide critical integration signals directing human physiological responses to the chemical milieu. To test our hypotheses, a progression of three specific aims will be deployed that include: 1) the structural analysis of crystallized CAR proteins;2) use of primary human hepatocyte culture models to enable receptor-driven transcriptional profiling, target gene interactions, and assessment of the dynamics of receptor intracellular localization;and, 3) humanized transgenic mouse investigations to analyze the transcriptional controls modulated by the receptors in vivo, and the phenotypic impact of receptor expression within a series of serum markers. We predict that the respective modulation of genomic programs and the resulting signaling circuitry controlled by the variant CARs have critical functional implications for human health, determining outcomes such as drug-drug interactions, drug and bile acid induced hepatotoxicity, carcinogen and steroid metabolism, and the regulation of lipid and energy homeostasis. The results of the proposed research will contribute important new advances and insights regarding the role of the CAR nuclear receptors as direct modulators of the dynamic gene regulatory networks that determine toxicological and physiological responses to both xenobiotic and endogenous substances.

Public Health Relevance

In this research program, our studies will characterize the roles of a novel series of receptor proteins that interact with pharmaceuticals and environmental chemicals and function to regulate the liver's capacity to metabolize substances. These receptors are termed constitutive androstane receptors and are part of a battery of sensing proteins that exist with liver cells to assist in processing the nature of the cell's chemical environment so that it can better tune its ability to detoxify chemicals we are exposed to.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066411-07
Application #
8197094
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2002-09-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$313,766
Indirect Cost
$76,166
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Hao, Ruixin; Su, Shengzhong; Wan, Yinan et al. (2016) Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver. Biochim Biophys Acta 1859:1228-37
Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J et al. (2016) Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. J Biol Chem 291:15378-87
Laurenzana, Elizabeth M; Coslo, Denise M; Vigilar, M Veronica et al. (2016) Activation of the Constitutive Androstane Receptor by Monophthalates. Chem Res Toxicol 29:1651-1661
Wahlang, Banrida; Falkner, K Cameron; Clair, Heather B et al. (2014) Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci 140:283-97
Currie, Richard A; Peffer, Richard C; Goetz, Amber K et al. (2014) Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action. Toxicology 321:80-8
Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong et al. (2014) Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells. Toxicology 326:18-24
Chen, Tao; Laurenzana, Elizabeth M; Coslo, Denise M et al. (2014) Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor. Biochem J 458:95-107
Elcombe, Clifford R; Peffer, Richard C; Wolf, Douglas C et al. (2014) Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol 44:64-82
Chen, Fengming; Zamule, Stephanie M; Coslo, Denise M et al. (2013) The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells. Dev Biol 384:155-65
Laurenzana, Elizabeth M; Chen, Tao; Kannuswamy, Malavika et al. (2012) The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3). Mol Pharmacol 82:918-28

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