Review
Targeting xenobiotic receptors PXR and CAR for metabolic diseases

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The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two closely related and liver-enriched nuclear hormone receptors originally defined as xenobiotic receptors. Recently, an increasing body of evidence suggests that PXR and CAR also have endobiotic functions that impact glucose and lipid metabolism, as well as the pathogenesis of metabolic diseases. These new findings suggest that PXR and CAR not only regulate the transcription of drug-metabolizing enzymes and transporters, but also orchestrate energy metabolism and immune responses to accommodate stresses caused by xenobiotic exposures. The effectiveness of targeting PXR and CAR in the treatment of metabolic disorders, such as obesity, type 2 diabetes (T2D), dyslipidemia, and atherosclerosis, have been suggested in animal models. However, translation of these basic research results into clinical applications may require further investigation to determine the human relevance, and to obtain better understanding of the mechanisms through which PXR and CAR affect energy metabolism. Given a wide variety of natural or synthetic compounds that are PXR and CAR modulators, it is hoped that these two ‘xenobiotic receptors’ can be harnessed for therapeutic potentials in managing metabolic diseases.

Introduction

Metabolizing and eliminating toxic chemicals in the liver and intestine is the first-line defensive system, which is conserved in nearly all animals from fruit flies to humans. Many of the chemicals absorbed into our body are lipophilic and need to be transformed into more water-soluble forms before being excreted. PXR (SXR, NR1I2) and CAR (NR1I3), two members of the superfamily of nuclear receptors, have been well recognized as ‘xenobiotic sensors’ that transcriptionally regulate the expression of Phase I and Phase II drug/xenobiotic metabolizing enzymes and transporters. In addition to its function in drug metabolism, the liver is also one of the major organs that regulate glucose and lipid metabolism. Recently, increasing evidence has suggested the endobiotic functions of PXR and CAR in regulating energy homeostasis under both physiological and pathological conditions. Furthermore, the immune modulating effect of PXR in the intestine and on immune cells also suggests a potential mechanism through which PXR may impact metabolic diseases. This review mainly focuses on the recent findings on the functions of PXR and CAR in energy homeostasis and immune regulation, and the implications of these functions in metabolic diseases.

Section snippets

PXR and CAR in hyperglycemia and diabetes

T2D is a chronic disease characterized by uncontrolled hyperglycemia caused by insulin resistance in the initial stage followed by pancreatic β cell failure at later stages. The liver plays a critical role in maintaining blood glucose homeostasis by controlling hepatic glucose production (HGP) in response to hormones, such as insulin, glucagon, and adipokines. In T2D, the high levels of HGP and the inability of insulin to suppress hepatic glucose output are major contributors to both fasting

PXR and CAR in obesity and dyslipidemia

Excess nutrients and sedentary life style have led to the prevalence of obesity as a major health problem worldwide. The most common consequence of obesity is dyslipidemia, characterized by elevations of very low-density lipoprotein (VLDL) triglycerides and low-density lipoprotein (LDL) cholesterol and reduced concentrations of high-density lipoprotein (HDL) cholesterol, which significantly increased the risk of cardiovascular diseases, such as hypertension and atherosclerosis. Obesity also

Anti-inflammatory activity of PXR and its potential role in metabolic disease

Excess nutrients and obesity can lead to a low-grade activation of the innate immune system, and this chronic low-grade inflammation has been widely recognized to play critical roles in the initiation, propagation, and development of metabolic diseases. There is emerging evidence suggesting a function of PXR in immune responses, and PXR agonists may have potentials in inhibiting inflammation related diseases, including metabolic disease. PXR activation was known to suppress the activity of

Challenges in harnessing the therapeutic potentials PXR and CAR in metabolic disease

CAR activation seemed to ameliorate most hallmarks of metabolic syndromes, including hyperglycemia, dyslipidemia, increased adiposity, and hypertension, which confer CAR desired properties as a promising therapeutic target for metabolic disease. However, a safety issue may be a hurdle for utilizing current CAR agonists for the treatment of metabolic disease. CAR activation by PB or its derivative TCPOBOP in mice has been known to mediate the hepatic toxicity of acetaminophen [46]. Activation of

Concluding remarks

Recent findings from many laboratories have clearly suggested that PXR and CAR regulate not only drug metabolism, but also energy homeostasis and immune response, which may establish PXR and CAR as potential therapeutic targets for metabolic diseases. The endobiotic functions of PXR and CAR, including those implicated in metabolic diseases, are expected to drive these ‘old’ xenobiotic receptors into a new era. As summarized in Figure 1, targeting both gluconeogenic and lipogenic pathways by CAR

Acknowledgments

The original results from our laboratories that are described in this chapter were generated with the support of NIH grants ES012479, ES014626, CA107011, DK076962, DK083952, and ES019629 (to W.X.). J.G. was supported by a Molecular Pharmacology Fellowship from the Department of Pharmacology and Chemical Biology, University of Pittsburgh.

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