Trends in Endocrinology & Metabolism
ReviewPXR and CAR in energy metabolism
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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2022, Journal of Nutritional BiochemistryCitation Excerpt :PXR and CAR were also able to induce enzymes, such as the downstream CYP2B and CYP3A family members, and CYP1 family enzymes were mediated by AHR, which are markers of AHR [72,73]. Further, PXR was sensitive for detecting toxic substances, which regulated CYP3A4 expression to eliminate these toxicants [74,75]. The transcription of CYP isoforms inhibition and CYPs disorder could cause the accumulation of Cd, therefore exacerbating the renal injury of chickens [54].