Nuclear receptors in lipid metabolism and toxicity (WP139)

Rattus norvegicus

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.


Sebastien Burel , Kristina Hanspers , Susan Coort , Cizar , Daniela Digles , and Martina Summer-Kutmon


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Rattus norvegicus



Pathway Ontology

lipid metabolic pathway


Label Type Compact URI Comment
Fatty Acids Metabolite chebi:35366
Cholesterol Metabolite hmdb:HMDB0000067
7-Dehydrocholesterol Metabolite hmdb:HMDB0000032
Calcitriol Metabolite hmdb:HMDB0001903
Bile Acids Metabolite chebi:3098
Retinoic acid Metabolite hmdb:HMDB0001852
Lanosterol Metabolite hmdb:HMDB0001251
Isoprenoids Metabolite chebi:24913
Abca1 GeneProduct ncbigene:313210
Ppara GeneProduct ncbigene:25747
ABCC2 GeneProduct ncbigene:25303
Pparg GeneProduct ncbigene:25664
Nr1i2 GeneProduct ncbigene:84385
ABCB11 GeneProduct ncbigene:83569
Rara GeneProduct ncbigene:24705
Cyp8b1 GeneProduct ncbigene:81924
Cyp1a2 GeneProduct ncbigene:24297
Abcg5 GeneProduct ncbigene:114628
Abcg1 GeneProduct ncbigene:85264
Cyp2c GeneProduct ncbigene:29277
Abca1 GeneProduct ncbigene:313210
Cyp26a1 GeneProduct ncbigene:154985
Nr1i3 GeneProduct ncbigene:65035
Vdr GeneProduct ncbigene:24873
Abcc3 GeneProduct ncbigene:140668
Cyp2b2 GeneProduct ncbigene:361523
Cyp7a1 GeneProduct ncbigene:25428
RARB GeneProduct ncbigene:24706
Cyp7a1 GeneProduct ncbigene:25428
Abca1 GeneProduct ncbigene:313210
CYP27B1 GeneProduct ncbigene:114700
Cyp2b2 GeneProduct ncbigene:361523
Rarg GeneProduct ncbigene:685072
Cyp4b1 GeneProduct ncbigene:24307
Abcb4 GeneProduct ncbigene:24891
Cyp24a1 GeneProduct ncbigene:25279
Nr1h3 GeneProduct ncbigene:58852
Cyp7a1 GeneProduct ncbigene:25428
Abcb1a GeneProduct ncbigene:170913
Nr1h4 GeneProduct ncbigene:60351 Farnesoid X-activated receptor
Cyp2e1 GeneProduct ncbigene:25086
Cyp2c GeneProduct ncbigene:29277
Abcd2 GeneProduct ncbigene:84356
Ppard GeneProduct ncbigene:25682
Abcd3 GeneProduct ncbigene:25270
Abcb1 GeneProduct ncbigene:170913
Cyp2c GeneProduct ncbigene:29277