Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism
- PMID: 20659512
- DOI: 10.1016/j.addr.2010.07.006
Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism
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.
Copyright © 2010 Elsevier B.V. All rights reserved.
Similar articles
-
The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.Exp Biol Med (Maywood). 2008 Oct;233(10):1191-201. doi: 10.3181/0802-MR-50. Epub 2008 Jun 5. Exp Biol Med (Maywood). 2008. PMID: 18535165 Free PMC article. Review.
-
Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR.Arch Biochem Biophys. 2005 Jan 15;433(2):387-96. doi: 10.1016/j.abb.2004.08.030. Arch Biochem Biophys. 2005. PMID: 15581595 Review.
-
Identification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3).Mol Pharmacol. 2008 Mar;73(3):891-9. doi: 10.1124/mol.107.040741. Epub 2007 Nov 30. Mol Pharmacol. 2008. PMID: 18055760
-
The emerging role of constitutive androstane receptor and its cross talk with liver X receptors and peroxisome proliferator-activated receptor A in lipid metabolism.Vitam Horm. 2013;91:243-58. doi: 10.1016/B978-0-12-407766-9.00010-9. Vitam Horm. 2013. PMID: 23374719 Review.
-
The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes.Prog Nucleic Acid Res Mol Biol. 2001;69:205-47. doi: 10.1016/s0079-6603(01)69048-2. Prog Nucleic Acid Res Mol Biol. 2001. PMID: 11550795 Review.
Cited by
-
Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses.Antioxidants (Basel). 2021 Aug 26;10(9):1352. doi: 10.3390/antiox10091352. Antioxidants (Basel). 2021. PMID: 34572984 Free PMC article. Review.
-
Computational Strategies for Assessing Adverse Outcome Pathways: Hepatic Steatosis as a Case Study.Int J Mol Sci. 2024 Oct 17;25(20):11154. doi: 10.3390/ijms252011154. Int J Mol Sci. 2024. PMID: 39456937 Free PMC article. Review.
-
A proteomics landscape of circadian clock in mouse liver.Nat Commun. 2018 Apr 19;9(1):1553. doi: 10.1038/s41467-018-03898-2. Nat Commun. 2018. PMID: 29674717 Free PMC article.
-
Understanding the Multiple Effects of PCBs on Lipid Metabolism.Diabetes Metab Syndr Obes. 2020 Oct 13;13:3691-3702. doi: 10.2147/DMSO.S264851. eCollection 2020. Diabetes Metab Syndr Obes. 2020. PMID: 33116719 Free PMC article. Review.
-
Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH.Metabolites. 2022 Mar 11;12(3):238. doi: 10.3390/metabo12030238. Metabolites. 2022. PMID: 35323681 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources