Atypical functions of xenobiotic receptors in lipid and glucose metabolism

Abstract

Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors, the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics. Emerging evidence suggests that "xenobiotic receptors" also have diverse endobiotic functions, including their effects on lipid metabolism and energy metabolism. Dyslipidemia is a major risk factor for cardiovascular disease, diabetes, obesity, metabolic syndrome, stroke, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Understanding the molecular mechanism by which transcriptional factors, including the xenobiotic receptors, regulate lipid homeostasis will help to develop preventive and therapeutic approaches. This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), in metabolic disorders, with a particular focus on their effects on lipid and glucose metabolism. Collectively, the literatures suggest the potential values of AhR, PXR and CAR as therapeutic targets for the treatment of NAFLD, NASH, obesity and diabetes, and cardiovascular diseases.

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

Figure 1:

Summary of fatty acid and triglyceride metabolism in the liver. The fatty acids are originated from de novo synthesis, diet, or adipose tissue. LPL and ATGL catalyze the hydrolysis of the triglyceride in the chylomicrons and adipocytes. Carbohydrate feeding promotes de novo lipogenesis by inducing the key enzymes FAS, SCD-1, and ACC-1 through the master lipogenic transcriptional factor SREBP-1c. FATP or FAT/CD36 can also take up circulating fatty acids into the liver. Liver fatty acids can be oxidized in mitochondria to produce energy and ketone bodies by CPT and HMGCS, or re-esterified to TG and exported as VLDL. Increased fatty acid synthesis and uptake or decreased fatty acid β-oxidation and triglyceride secretion may cause hepatic steatosis. FFA, free fatty acid; LPL, lipoprotein lipase; ATGL, adipocyte triglyceride hydrolase; FAS, fatty acid synthase; SCD-1, stearoyl CoA desaturase 1; ACC-1, acetyl coenzyme A carboxylase 1; SREBP-1c, sterol response element binding protein-1c; FATP, Fatty acid transport protein; FAT/CD36, fatty acid translocase; CPT, carnitine palmitoyl transferase; HMGCS, 3-hydroxy-3-methylglutaryl-CoA synthase; TG, triglyceride; VLDL, very-low-density lipoproteins.

Figure 2:

Overview of cholesterol and lipoprotein metabolism. FCT is the transporter of triglycerides and cholesterol to peripheral tissues. Dietary fats and cholesterol are transported to the liver by chylomicrons. The liver packages cholesterol and triglycerides into VLDL and VLDL is exported to the periphery with the help of LPL, LCAT, and LDLR. RCT is a process for the recycling of cholesterol from periphery tissues back to the liver. The process of HDL maturation begins with the secretion of lipid-poor apoA-I and nascent discoid-like HDL particles by the liver and intestine, followed by acquisition of cholesterol and phospholipids efflux mediated by the ATP-binding cassette transporter family member ABCA1. Cholesterol carried by is HDL matured by LCAT and taken up into the liver via SR-BI or redistributed to the apo-B containing particles VLDL and LDL through the action of CETP. Cholesterol in the liver can be excreted directly into bile via the ABCG5/8. FCT, forward cholesterol transport; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein; LCAT, lecithincholesterol acetyltransferase; LDLR, LDL receptor; RCT, reverse cholesterol transport; HDL, high-density lipoprotein; ABC, ATP-binding cassette; SR-BI, scavenge receptor B-I; CETP, cholesteryl ester transfer protein; ABCG5/8, ATP-binding cassette sub-family G member 5/8.

Figure 3:

Summary of the major responsive genes of AhR, PXR, and CAR involved in lipid and glucose metabolism. Both xenobiotics and endobiotics can activate the AhR-Arnt, PXR-RXR, and CAR-RXR functional heterodimers, which bind to a DRE, PXRE, or CARE within the promoter region of target genes. This binding results in the regulation of gene expression. Note that the listed target genes that are either up-or down-regulated here are not complete and not intended to specify a particular cell type. PAHs, polycyclic aromatic hydrocarbons; HAHs, halogenated aromatic hydrocarbons; AA, amino acids; LDLs, low-density lipoprotein; PCN, pregnenolone-16α-carbonitrile; RIF, rifampicin; TCPOBOP, 1,4-Bis (2-[3,5-dichloropyridyloxy]) benzene; CITCO, 6-(4-chlorophenyl) imidazo [2, 1-b] [1, 3] thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime. Fatp, fatty acid transport protein; Atgl, adipocyte triglyceride hydrolase; Fgf21, fibroblast growth factor 21; Fasn, fatty acid synthase; Scd-1, stearoyl CoA desaturase 1; Acc-1, acetyl coenzyme A carboxylase 1; Srebp-1c, sterol response element binding protein-1c; Pparα, peroxisome proliferator-activated receptor α; Acox1, Acyl-CoA Oxidase 1; Pepck, phosphoenolpyruvate carboxykinase; G6Pase, glucose 6-phosphatase; Glut4, glucose transporter 4; SOD2, superoxide dismutase 2; SIRT3, sirtuin deacetylase 3; Pparγ2, peroxisome proliferator-activated receptor γ2; S14, thyroid hormone responsive spot 14 protein; Cpt-1a, carnitine palmitoyltransferase 1a; Hmgcs2, 3-hydroxy-3-methylglutarate-CoA synthase; Abca1, ATP-binding cassette transporter family member A1; LCAT, lecithin-cholesterol acetyltransferase; PLTP, phospholipid transfer protein; SR-BI, scavenge receptor B-I; Glut2, glucose transporter 2; Pgc-1α, peroxisome proliferative activated receptor-γ co-activator 1α; AhR, aryl hydrocarbon receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; DRE, dioxin response element; PXRE, PXR response element; CARE, CAR response element; ABC, ATP-binding cassette.