Review
PXR and CAR in energy metabolism

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The nuclear receptors pregnane X receptor (PXR, or NR1I2) and constitutive androstane receptor (CAR, or NR1I3) were originally identified as xenosensors that regulate the expression of Phase I and Phase II drug-metabolizing enzymes and transporters. Recent results suggest that PXR and CAR also have important endobiotic roles in energy metabolism by affecting the metabolism of fatty acids, lipids and glucose. PXR and CAR exert their effects on energy metabolism through direct gene regulation or through crosstalk with other transcriptional regulators. This review focuses on the roles of CAR and PXR in energy metabolism and offers a perspective on whether PXR and CAR represent novel therapeutic targets for the management of metabolic syndrome.

Section snippets

Energy metabolism and the role of nuclear receptors

The liver is an essential organ in metabolic homeostasis. Disruption of lipid and glucose metabolism in the liver might trigger various cardiovascular and metabolic diseases, such as atherosclerosis, type II diabetes, obesity and insulin resistance. The liver maintains triglyceride homeostasis by storing circulating fatty acids as triglycerides, oxidizing fatty acids and secreting triglycerides as very-low-density lipoproteins. Under normal conditions, the major sources of energy to maintain

PXR and CAR as xenobiotic receptors

PXR and CAR are members of the orphan NR subfamily. PXR and CAR were originally defined as xenobiotic receptors, regulating the expression of drug-metabolizing enzymes and transporters as adaptive responses to prevent the accumulation of toxic chemicals in the body. Like most other NRs, PXR and CAR have an N-terminal DNA-binding domain and a C-terminal ligand-binding domain (LBD). PXR and CAR regulate gene expression by forming heterodimers with the retinoid X receptor and, subsequently,

PXR in lipid and glucose metabolism

Recently, it has been shown that PXR affects lipid homeostasis [22] (Figure 2a). Transgenic mice expressing constitutively activated PXR show hepatomegaly and marked hepatic steatosis. Furthermore, treatment of hPXR humanized mice with the hPXR agonist RIF causes hepatic triglyceride accumulation. Unlike the liver X receptor, which promotes hepatic lipogenesis by activating the lipogenic transcription factor sterol regulatory element binding protein (SREBP)-1, PXR induces lipogenesis in a

CAR in energy homeostasis

Recent studies have linked CAR to lipid metabolism. Activation of CAR (and PXR) might suppress lipid metabolism and lower serum triglyceride levels by reducing levels of SREBP-1, a master regulator of lipid metabolism [24]. The inhibitory effects of CAR on lipid metabolism might also be attributed to induction of Insig-1, a protein with anti-lipogenic properties [24] (Figure 3a). Insig-1 is a protein of the endoplasmic reticulum (ER) that blocks proteolytic activation of SREBPs. When cellular

Concluding remarks

Recent findings from many laboratories have clearly suggested that PXR and CAR regulate not only drug metabolism but also energy homeostasis. PXR and CAR contribute to energy homeostasis through their effects on hepatic lipogenesis, fatty acid β-oxidation and gluconeogenesis. It has also become clear that in their inhibition of lipogenesis and gluconeogenesis, PXR and CAR do not act alone but, rather, interact with many other transcription factors and co-regulators, including PPARα, PGC-1α,

Acknowledgements

The original research of ours described in this article was supported, in part, by NIH grants ES012479, ES014626 and CA107011.

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