Nuclear receptors in lipid metabolism and toxicity (WP755)

Gallus gallus

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 , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , and Lauren J. Dupuis


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Gallus gallus



Pathway Ontology

lipid metabolic pathway


Label Type Compact URI Comment
Fatty Acids Metabolite chebi:35366
Bile Acids Metabolite chebi:3098
Retinoic acid Metabolite hmdb:HMDB0001852
Lanosterol Metabolite chebi:16521
Isoprenoids Metabolite chebi:24913
ABCA1 GeneProduct ncbigene:373945
CYP3A80 GeneProduct ncbigene:416477
PPARA GeneProduct ncbigene:374120
ABCC2 GeneProduct ncbigene:423828
PPARG GeneProduct ncbigene:373928
ABCB11 GeneProduct ncbigene:424170
RARA GeneProduct ncbigene:395213
CYP8B GeneProduct ncbigene:425055
CYP1A2 GeneProduct ncbigene:414856
ABCG5 GeneProduct ncbigene:421401
ABCG1 GeneProduct ncbigene:418533
ABCA1 GeneProduct ncbigene:373945
CYP3A80 GeneProduct ncbigene:416477
CYP26A1 GeneProduct ncbigene:408183
NR1I3 GeneProduct ncbigene:395439
VDR GeneProduct ncbigene:395988
ABCC3 GeneProduct ncbigene:422099
CYP4B1 GeneProduct ncbigene:424618
CYP7A1 GeneProduct ncbigene:414834
RARB GeneProduct ncbigene:396266
CYP7A1 GeneProduct ncbigene:414834
ABCA1 GeneProduct ncbigene:373945
CYP4B1 GeneProduct ncbigene:424618
CYP3A80 GeneProduct ncbigene:416477
CYP24A1 GeneProduct ncbigene:395827
NR1H3 GeneProduct ncbigene:395221
CYP7A1 GeneProduct ncbigene:414834
NR1H4 GeneProduct ncbigene:373902 Farnesoid X-activated receptor
ABCD2 GeneProduct ncbigene:417694
PPARD GeneProduct ncbigene:395479
ABCD3 GeneProduct ncbigene:424487
ABCB1 GeneProduct ncbigene:420534