Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

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.

Keywords: NR1I3; constitutive androstane receptor; endocrine disruption; glucose metabolism; lipid metabolism; metabolic disruptors.

Figure 1

Schematic overview of key regulatory processes affected by CAR. CAR activation modulates key metabolic processes, such as glucose and lipid metabolism and bile acid synthesis via several mechanisms and pathways (as detailed in the main text). These effects depend in part on sex, nutritional status, or metabolic challenge used in animal studies. CAR-mediated induction of genes involved in glucose uptake and utilization (e.g., hexokinase, PGD) generates NADPH, which in turn supports xenobiotic metabolism. Through regulation of thyroid hormone levels, CAR can contribute to energy expenditure and weight loss. CAR alters the expression of genes associated with cell proliferation and oncogenic signaling in rodents. Positive outcomes are depicted with green, ambivalent outcomes with yellow, and adverse outcomes with orange color.