AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors

Abstract

Traditionally, xenobiotic receptors are known for their role in chemical sensing and detoxification, as receptor activation regulates the expression of various key enzymes and receptors. However, recent studies have highlighted that xenobiotic receptors also play a key role in the regulation of lipid metabolism and therefore function also as metabolic sensors. Since dyslipidemia is a major risk factor for various cardiometabolic diseases, like atherosclerosis and non-alcoholic fatty liver disease, it is of major importance to understand the molecular mechanisms that are regulated by xenobiotic receptors. In this review, three major xenobiotic receptors will be discussed, being the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Specifically, this review will focus on recent insights into the metabolic functions of these receptors, especially in the field of lipid metabolism and the associated dyslipidemia.

Keywords: aryl hydrocarbon receptor; cardiometabolic diseases; constitutive androstane receptor; lipid metabolism; pregnane X receptor; xenobiotic receptors.

Figure 1

Main pathways of lipid metabolism. The exogenous pathway begins with the transport of ingested dietary lipids from the intestine to, for example, muscles and adipose tissue via chylomicrons, and the resulting chylomicron remnants transport the remaining lipids to the liver. The endogenous pathway starts in the liver with the synthesis of VLDL by conveying triglycerides and cholesterol esters in the endoplasmic reticulum to newly synthesized apoB-100 to form the core of VLDL. As VLDL circulates through the bloodstream, triglycerides are removed from VLDL, making it denser and more cholesterol-rich, eventually transforming into LDL. LDL primarily carries cholesterol to peripheral tissues, such as muscle, heart or adipose tissue, while HDL is responsible for reverse cholesterol transport, where excess cholesterol is transported from peripheral tissues back to the liver. ApoA-I: apolipoprotein A-I; ApoB-100: apolipoprotein B-100; CD36: cluster of differentiation 36; CE: cholesterol esters; CETP: cholesteryl ester transfer protein; HDL: high-density lipoprotein; IDL: intermediate-density lipoprotein; LCAT: lecithin cholesterol acyl transferase; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; LPL: lipoprotein lipase; SR-BI: scavenger receptor B-I; TG: triglyceride; VLDL: very low-density lipoprotein. Figure created with BioRender.com.

Figure 2

Mechanism of xenobiotic receptor activation. (Left panel): In the cytoplasm, AhR is bound by Hsp90, AIP, the co-chaperone p23 and protein kinase SRC. After ligand binding, with either exogenous ligands or endogenous ligands such as tryptophane metabolites, the AhR complex releases AIP and translocates to the nucleus, where the rest of the cofactors dissociate from AhR, enabling ARNT to heterodimerize with AhR. The AhR–ARNT complex then binds to the DNA and regulates the gene expression of several genes, such as CYP1A1, CYP1B1 or AHRR. AHRR can negatively regulate AhR by inhibiting the AhR–ARNT complex. (Middle panel): Mechanism of PXR activation. In the cytoplasm, PXR forms a complex with Hsp90 and CCRP, while non-activated PXR in the nucleus is bound to NcoR1 and SMRT. Upon receptor activation, PXR dissociates from its complex and translocates into the nucleus, where it binds to SRC-1 and GRIP1. Together with these coactivators, PXR heterodimerizes with RXR and binds to a PXR response element to induce target gene expression. (Right panel): CAR signaling. CAR is located in the cytoplasm, where it is bound to CCR and HSP90 in its inactive state. In the direct activation pathway, ligand binding activates PP2A, which dephosphorylates CAR, resulting in the dissociation of its co-chaperones. The activated CAR translocates into the nucleus, where it heterodimerizes with RXR and binds to the PBREM to induce target gene expression. In the indirect pathway (highlighted with green and red arrows), specific ligands of the Car can inhibit the binding of EGF to the EGFR. This results in the dephosphorylation of p-ERK and simultaneously the dephosphorylation of RACK. RACK activates PP2A and the dephosphorylated ERK dissociates from the CAR complex, enabling its activation by PP2A. AhR: aryl hydrocarbon receptor; AHRR: aryl hydrocarbon receptor repressor; AIP: AhR interacting protein; ARNT: aryl hydrocarbon receptor nuclear translocator; CAR: constitutive androstane receptor; CCRP: CAR cytoplasmic retention protein; CYP1A1: cytochrome P450 family 1 subfamily A member 1; CYP1B1: cytochrome P450 family 1 subfamily B member 1; EGF: epidermal growth factor; EGFR: EGF receptor; ERK: extracellular signal-regulated kinase, p-ERK: phosphorylated extracellular signal-regulated kinase; GRIP1: glucocorticoid receptor interacting protein 1; Hsp90: heat shock protein 90; NcoR1: nuclear receptor corepressor 1; P: phosphate; PBREM: phenobarbital responsive enhancer module; PP2A: protein phosphatase 2A; PXR: pregnane X receptor; PXRE: PXR-responsive element; RACK: receptor for activated C kinase 1; p-RACK: phosphorylated receptor for activated C kinase 1; RXR: retinoid X receptor; SMRT: silencing mediator of retinoid and thyroid receptors; SRC-1: steroid receptor coactivator 1; XRE: xenobiotic response element. Figure created with BioRender.com.

Figure 3

Effects of xenobiotic receptor activation on lipid metabolism. Activation of AhR (left) by ligands such as halogenated aromatic hydrocarbons leads to changes in gene transcription, which affects the lipid metabolism in various ways. PXR (middle) and CAR (right) share many ligands; however, their signaling pathways occur based on different cofactors. Nevertheless, both pathways result in similarly altered gene transcription of, for example, phase I and II enzymes. The activation of both receptors impacts lipid metabolism, targeting partly similar but also specific parts of lipid metabolism. Disruptions in lipid signaling can contribute to the development of CMDs, assigning the xenobiotic receptors a more metabolic sensing role. AhR: aryl hydrocarbon receptor; AHRR: aryl hydrocarbon receptor repressor; ARNT: aryl hydrocarbon receptor nuclear translocator; CAR: constitutive androstane receptor; CYP1A1: cytochrome P450 family 1 subfamily A member 1; CYP1B1: cytochrome P450 family 1 subfamily B member 1; GRIP1: glucocorticoid receptor interacting protein 1; NAFLD: non-alcoholic fatty liver disease; PBREM: phenobarbital-responsive enhancer module; PXR: pregnane X receptor; PXRE: PXR-responsive element; RXR: retinoid X receptor; SRC1: steroid receptor coactivator 1; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin; XRE: xenobiotic response element. Figure created with BioRender.com.