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Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

1
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland
2
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland
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Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Campus Box 7569, Chapel Hill, NC 27599-7569, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2306; https://doi.org/10.3390/cells9102306
Received: 15 September 2020 / Revised: 13 October 2020 / Accepted: 13 October 2020 / Published: 15 October 2020
(This article belongs to the Special Issue The Xenobiotic Receptors CAR and PXR in Health and Disease)
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein. View Full-Text
Keywords: endocrine disruption; metabolic disruptors; constitutive androstane receptor; NR1I3; glucose metabolism; lipid metabolism endocrine disruption; metabolic disruptors; constitutive androstane receptor; NR1I3; glucose metabolism; lipid metabolism
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Küblbeck, J.; Niskanen, J.; Honkakoski, P. Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR. Cells 2020, 9, 2306.

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