Noncanonical Constitutive Androstane Receptor Signaling in Gene Regulation

Yuliya A. Pustylnyak,Vladimir O. Pustylnyak,Lyudmila F. Gulyaeva

doi:10.3390/ijms21186735

Abstract

The constitutive androstane receptor (CAR, NR1I3) is extremely important for the regulation of many physiological processes, especially xenobiotic (drug) metabolism and transporters. CAR differs from steroid hormone receptors in that it can be activated using structurally unrelated chemicals, both through direct ligand-binding and ligand-independent (indirect) mechanisms. By binding to specific responsive elements on DNA, CAR increases the expression of its target genes encoding drug-metabolizing enzymes and transporters. Therefore, CAR is mainly characterized as a ligand-dependent or ligand-independent transcription factor, and the induction of gene expression is considered the canonical mode of CAR action. Consistent with its central role in xenobiotic metabolism, CAR signaling includes a collection of mechanisms that are employed alongside the core transcriptional machinery of the receptor. These so-called noncanonical CAR pathways allow the receptor to coordinate the regulation of many aspects of cell biology. In this mini-review, we review noncanonical CAR signaling, paying special attention to the role of CAR in energy homeostasis and cell proliferation.

Highlights

The constitutive androstane receptor (CAR, NR1I3) is a member of the nuclear receptor superfamily (NR), which includes steroid, retinoid, and thyroid hormone receptors [1]
CAR was originally characterized as a xenosensor that induces the expression of the CYP2B gene, which is involved in the biotransformation of a wide range of xenobiotics, including drugs [9,10]
The expression of these genes is regulated by the transcription factor forkhead box O1 (FoxO1), which binds to the insulin-responsible sequence (IRS)

Summary

Introduction

The constitutive androstane receptor (CAR, NR1I3) is a member of the nuclear receptor superfamily (NR), which includes steroid, retinoid, and thyroid hormone receptors [1] Members of this superfamily play key roles in almost all aspects of development and physiology, as they function as ligand-activated transcription factors. The ability of some ligands to bind to the receptor remains a matter of discussion, since only two compounds— 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and 6-(4-chlorophenyl) imidazo-[2,1-b][1,3] thiazole-5-carbaldehyde-O- (3,4-dichlorobenzyl)oxime (CITCO)—display a direct interaction with the CAR ligand-binding pocket. The affinity of these compounds for CAR varies significantly between species. This mini-review contains the recent progress in our understanding of noncanonical CAR signaling and how it coordinates the regulation of several aspects of the biochemistry of cells

Activation of CAR Nuclear Translocation

Canonical CAR Pathway

Noncanonical CAR Signaling in Gluconeogenic Gene Regulation

Noncanonical CAR Signaling in Hepatocyte Proliferation

Findings

Conclusions