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Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR
Jenni Küblbeck1,2, Jonna Niskanen2, Paavo Honkakoski2,3
1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland.
Abstract:
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.
Insights
The constitutive androstane receptor (CAR) activates key enzymes for clearing molecules. This review explores CAR
Area of Science:
- Endocrinology
- Toxicology
- Metabolism
Background:
- The constitutive androstane receptor (CAR; NR1I3) is a master regulator of xenobiotic metabolism.
- CAR influences hepatic glucose and lipid metabolism, cell communication, proliferation, and liver tumor development.
- Endocrine-disrupting chemicals (EDCs) are linked to metabolic disorders like diabetes, obesity, and fatty liver disease.
Purpose of the Study:
- To review the role of CAR in mediating adverse metabolic effects caused by EDCs.
- To discuss CAR's function as a xenobiotic sensor and its ligand selectivity.
Main Methods:
- Literature review of studies on CAR, xenobiotics, and metabolic effects.
- Analysis of species differences in CAR activation and ligand binding.
- Examination of evidence linking CAR to EDC-induced metabolic alterations.
Main Results:
- CAR activation by xenobiotics is a key mechanism in EDC-induced metabolic disruption.
- Species-specific differences in CAR function impact its role in xenobiotic response.
- CAR plays a significant role in regulating hepatic metabolism and its dysregulation by EDCs.
Conclusions:
- CAR is a critical mediator of EDC-induced metabolic diseases.
- Understanding CAR's mechanisms is vital for addressing health effects of EDCs.
- Further research into CAR-ligand interactions and species differences is warranted.
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