Nuclear receptors in lipid metabolism and toxicity

Nuclear receptors are transcription factors that are activated upon binding to its ligands. Initially, they had been classified as classic endocrine nuclear hormone receptors and orphan receptors. However, further studies have led to the identification of lipid ligands for some of these adopted orphan receptors, which are responsible for lipid metabolism, storage or elimination. One of the characteristics of these receptors is that they act by forming heterodimers with retinoid X receptor (RXR). The receptors include peroxisome proliferators-Activated receptors (PPARs) for fatty acids, liver X receptor (LCR) for oxysterols, Farnesoid X receptors (FXR) for bile acids and steroid xenobiotic receptor/X receptor (SXR/PXR or Nsil2) for xenobiotics. Other orphan receptors also require RXR for its functions are vitamin D receptor (VDR) for vitamin D and retinoic acid receptor (RAR) for retinoid acids, although these receptors are not involved in lipid metabolism. Upon binding to various ligands, three classes of proteins are synthesized including lipid binding proteins, the ATP-binding cassette (ABC) transporters and cytochrome P450 member proteins which catalyzes lipid anabolism, metabolism and elimination. In addition to lipid metabolism, some members of the cytochrome P450 family genes are responsible for activation of procarcinogens, detoxification of environmental toxins and metabolism of drugs and xenobiotics. In particular, CAR, Nsil2 and recently identified VDR are important in up-regulation of these cytochromes. Of all the human cytochrome P450 genes, only a few CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 account for most toxicity effects, specifically CYP3A is responsible for clearing approximately half of the clinically prescribed drugs. For instance, acetaminophen, one of the most commonly used drug, is toxic in high doses due to the activation of CAR and the drugs subsequent conversion to acetyl-p-benzoquinone imine (NAPQI) by CYP1A2, CYP2E1 and CYP3A.

核受体是一类在与其配体结合后被激活的转录因子。起初，它们被归类为经典内分泌核激素受体和孤儿受体。然而，进一步的研究揭示了某些被采纳的孤儿受体具有脂质配体，这些配体负责脂质代谢、储存或排泄。这些受体的一个特点是它们通过与视黄酸X受体（RXR）形成异源二聚体而发挥作用。这些受体包括过氧化物酶体增殖激活受体（PPARs）对脂肪酸、肝脏X受体（LCR）对氧化固醇、佛伦索伊德X受体（FXR）对胆汁酸以及外源物受体/X受体（SXR/PXR或Nsil2）对外源物。其他孤儿受体也依赖于RXR以实现其功能，例如维生素D受体（VDR）对维生素D和视黄酸受体（RAR）对视黄酸，尽管这些受体不参与脂质代谢。与各种配体结合后，会合成三类蛋白质，包括脂质结合蛋白、ATP结合 cassette（ABC）转运蛋白和细胞色素P450家族成员蛋白，后者催化脂质合成、代谢和排泄。除了脂质代谢外，细胞色素P450家族的一些基因成员还负责前致癌物的活化、环境毒素的解毒以及药物和外源物的代谢。特别是，CAR、Nsil2以及最近发现的VDR在提高这些细胞色素的表达水平方面发挥着重要作用。在所有人类细胞色素P450基因中，只有少数CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A基因对大多数毒性效应负有责任，其中CYP3A负责清除约一半的临床处方药物。例如，对乙酰氨基酚，这是一种最常使用的药物之一，在高剂量时由于CAR的激活以及CYP1A2、CYP2E1和CYP3A将药物转化为乙酰-p-苯醌亚胺（NAPQI）而具有毒性。