Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR.
Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drug-metabolizing cytochromes P450 (CYPs). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin, and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bile-acid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.
Handschin
Christoph
C
Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA. christoph_handschin@dfci.harvard.edu <christoph_handschin@dfci.harvard.edu>
Meyer
Urs A
UA
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003001:Cloning, Molecular; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D010802:Phylogeny; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D001663:Bilirubin; D002784:Cholesterol; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics; D000099150:Receptor, Farnesoid X-Activated; C000605210:NR1H2 protein, human; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human