Elsevier

Advanced Drug Delivery Reviews

Volume 62, Issue 13, 30 October 2010, Pages 1316-1321
Advanced Drug Delivery Reviews

Functional crosstalk of CAR–LXR and ROR–LXR in drug metabolism and lipid metabolism

https://doi.org/10.1016/j.addr.2010.07.006Get rights and content

Abstract

Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and β isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, β and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR–LXR and ROR–LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism.

Introduction

The liver is an essential organ in metabolic homeostasis. Metabolic homeostasis includes those of the foreign substances or xenobiotics, as well as those of the endogenous chemicals or endobiotics. Xenobiotic homeostasis represents mammals' responses to xenobiotics, such as drugs and other obnoxious substances; whereas endobiotic homeostasis is the balanced production and elimination of endobiotics, such as lipids [1], [2]. Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic compounds. The superfamily of cytochromes P450 (CYPs) enzymes is the best studied class of enzymes in this task [3]. Lipids are essential for energy homeostasis, reproductive and organ physiology, and numerous aspects of cellular biology. Disruption of lipid metabolism in the liver might trigger various metabolic diseases, such as atherosclerosis, diabetes and obesity.

Nuclear receptors, a family of ligand-dependent transcriptional factors, play important roles in metabolic homeostasis. Most nuclear receptors contain an N-terminal DNA biding domain (DBD) and a C-terminal ligand binding domain (LBD). Nuclear receptors regulate gene expression by binding to their responsive elements present in target gene promoters. The nuclear receptor superfamily includes not only the classic endocrine receptors that mediate the actions of steroid hormones, thyroid hormones, and the fat-soluble vitamins A and D [4], but also a large number of so-called orphan nuclear receptors, whose ligands and physiological functions were initially unknown [5]. Over the last several years, many studies have elucidated the role of these orphan receptors in physiology and diseases. Among orphan receptors, it has been recognized that LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. RORs are known to play a role in tissue development, immune responses, and circadian rhythm. More recent reports suggested that in addition to their traditional functions, LXR, CAR and ROR can also impact other physiological pathways by crosstalking with each other. Specifically, LXR–CAR and ROR–LXR are found to be mutually suppressive, so these receptors can affect each others' activity and consequently affect the downstream events controlled by these receptors. This review will focus on the novel function of the crosstalk between RORs and LXRs and the crosstalk between CARs and LXRs in drug metabolism and lipid metabolism.

Section snippets

The sterol sensors LXRs

LXR was initially isolated from a human liver cDNA library as an orphan receptor [6]. There are two LXR isoforms in mammals, named LXRα (NR1H3) and LXRβ (NR1H2). High expression of LXRα is restricted to spleen, liver, adipose tissue, intestine, kidney and lung, whereas LXRβ is expressed in all tissues examined [6], [7], [8], [9]. Both LXRα and LXRβ function as heterodimers with the retinoid X receptor (RXR). The LXR/RXR heterodimers preferentially bind to LXR response element (LXRE) that

Crosstalk of RORs and LXRs in lipid metabolism

As discussed earlier, RORs and LXRs were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis [65]. The RORα–LXR crosstalk in lipid metabolism was initially suggested by the remarkable overlap in the pattern of genes affected in livers from the RORα null mice and LXR-activated mice. Activation of LXR in mice induced the expression of Est/Sult1e1, Sult2a9/2a1 and the fatty acid

Crosstalk of CAR and LXRs links drug metabolism and lipid metabolism

LXR and CAR are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. We have recently shown that LXRα and CAR are functionally related in vivo. Specifically, loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation; whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced

Conclusion remarks

Recent findings from many laboratories have clearly suggested that nuclear receptors LXR, CAR and ROR not only have their “traditional” functions, but also have interesting crosstalk in their participation of drug metabolism and lipid metabolism. The crosstalk of ROR-LXR and CAR-LXR and their potential implications in physiology are summarized in Fig. 1. The crosstalk among these receptors has implications in drug development and pathophysiology. For example, having known that sustained

Acknowledgement

This work was supported by grants (30870926 to Y.Z.) from the National Natural Science Foundation of China, grants from the CSCSE (2009), Key Laboratory of Beijing Normal University (2009), and Key Laboratory for Cell Proliferation and Regulation Biology, Ministry of Education (2009).

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Development of Novel Therapeutic Strategy by Regulating the Nuclear Hormone Receptors”.

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