Nuclear receptors in lipid metabolism and toxicity (WP1099)

Canis familiaris

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.


Kristina Hanspers , Egon Willighagen , and Daniela Digles


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Canis familiaris



Pathway Ontology

lipid metabolic pathway


Label Type Compact URI Comment
Xenobiotics Metabolite chebi:35703
Fatty Acids Metabolite chebi:35366
Cholesterol Metabolite cas:57-88-5
7-DehydroCholesterol Metabolite cas:434-16-2
Bile Acids Metabolite chebi:3098
Retinoic acid Metabolite hmdb:HMDB0001852
Acetyl CoA Metabolite cas:72-89-9
Lanosterol Metabolite chebi:16521
Isoprenoids Metabolite chebi:24913
ABCA1 GeneProduct ncbigene:481651
PPARA GeneProduct ncbigene:403654
ABCC2 GeneProduct ncbigene:403632
PPARG GeneProduct ncbigene:403606
NR1I2 GeneProduct ncbigene:403482
ABCB11 GeneProduct ncbigene:488390
RARA GeneProduct ncbigene:480526
LOC485619 GeneProduct ncbigene:485619
CYP1A2 GeneProduct ncbigene:494010
ABCG5 GeneProduct ncbigene:481354
ABCG1 GeneProduct ncbigene:487777
ABCA1 GeneProduct ncbigene:481651
CYP26A1 GeneProduct ncbigene:486804
NR1I3 GeneProduct ncbigene:488653
VDR GeneProduct ncbigene:486588
ABCC3 GeneProduct ncbigene:491084
CYP2B6 GeneProduct ncbigene:474177
CYP7A1 GeneProduct ncbigene:486962
RARB GeneProduct ncbigene:477045
CYP7A1 GeneProduct ncbigene:486962
ABCA1 GeneProduct ncbigene:481651
CYP27B1 GeneProduct ncbigene:481133
CYP2B6 GeneProduct ncbigene:474177
RARG GeneProduct ncbigene:486508
CYP4B1 GeneProduct ncbigene:608452
ABCB4 GeneProduct ncbigene:482284
CYP24A1 GeneProduct ncbigene:485935
NR1H3 GeneProduct ncbigene:483625
CYP7A1 GeneProduct ncbigene:486962
NR1H4 GeneProduct ncbigene:612928 Farnesoid X-activated receptor
CYP2E1 GeneProduct ncbigene:415128
ABCD2 GeneProduct ncbigene:477643
PPARD GeneProduct ncbigene:481756
ABCD3 GeneProduct ncbigene:479939
ABCB1 GeneProduct ncbigene:403879