Hukkanen Janne, Küblbeck Jenni, Hakkola Jukka, Rysä Jaana
Research Unit of Biomedicine and Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
Pharmacol Res. 2025 Sep;219:107892. doi: 10.1016/j.phrs.2025.107892. Epub 2025 Jul 31.
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were initially described as xenobiotic sensors, but an increasing number of studies have linked their activity to other important physiological processes including glucose and lipid metabolism, implying an expanded role as metabolic sensors. CAR and PXR are nuclear receptors, which share similarities in expression, ligand-specificity, and mechanism of transcriptional regulation but they have their distinct features as well. Together, they regulate a wide array of target genes, whose functions range from elimination of xenobiotics to energy metabolism. Both CAR and PXR have large ligand binding pockets, and especially the PXR pocket is flexible for structurally different chemicals. Consequently, CAR and PXR could have a role in mediating the harmful metabolic effects of drugs and environmental chemicals. Current knowledge supports a role for PXR in the regulation of lipid and cholesterol metabolism. The actions seem to be mostly unfavorable, since the activation of PXR has been shown to promote hepatic lipogenesis and hyperlipidemia, increase plasma cholesterol and impair hepatic LDL uptake. PXR and PXR-regulated circulating 4β-hydroxycholesterol may also influence blood pressure regulation. CAR, in contrast, tends to exert beneficial effects on lipid and glucose homeostasis, since CAR activation has been shown to reduce serum triglyceride and cholesterol levels and have anti-atherogenic properties. Here we review current knowledge on CAR and PXR as regulators of cardiometabolic functions, including glucose and lipid homeostasis, blood pressure regulation and atherosclerosis.
组成型雄烷受体（CAR）和孕烷X受体（PXR）最初被描述为外源性物质传感器，但越来越多的研究将它们的活性与包括葡萄糖和脂质代谢在内的其他重要生理过程联系起来，这意味着它们作为代谢传感器的作用得到了扩展。CAR和PXR是核受体，它们在表达、配体特异性和转录调控机制方面有相似之处，但也有各自独特的特征。它们共同调节一系列靶基因，其功能从外源性物质的清除到能量代谢。CAR和PXR都有较大的配体结合口袋，特别是PXR口袋对于结构不同的化学物质具有灵活性。因此，CAR和PXR可能在介导药物和环境化学物质的有害代谢效应中起作用。目前的知识支持PXR在脂质和胆固醇代谢调节中的作用。这些作用似乎大多是不利的，因为已证明PXR的激活会促进肝脏脂肪生成和高脂血症，增加血浆胆固醇并损害肝脏低密度脂蛋白摄取。PXR和PXR调节的循环4β-羟基胆固醇也可能影响血压调节。相比之下，CAR倾向于对脂质和葡萄糖稳态产生有益影响，因为已证明CAR的激活会降低血清甘油三酯和胆固醇水平并具有抗动脉粥样硬化特性。在此，我们综述了关于CAR和PXR作为心脏代谢功能调节剂的当前知识，包括葡萄糖和脂质稳态、血压调节和动脉粥样硬化。
