Nuclear receptors in lipid metabolism and toxicity (WP1326)

Danio rerio

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 , and Egon Willighagen


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Danio rerio



Pathway Ontology

lipid metabolic pathway


Label Type Compact URI Comment
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
cyp3a65 GeneProduct ncbigene:553969
abcc2 GeneProduct ncbigene:393561
pparg GeneProduct ncbigene:557037
nr1i2 GeneProduct ncbigene:565875
abcb11b GeneProduct ncbigene:571189
abcg5 GeneProduct ncbigene:557317
abcg1 GeneProduct ncbigene:556979
cyp3a65 GeneProduct ncbigene:553969
cyp26a1 GeneProduct ncbigene:30381
cyp7a1a GeneProduct ncbigene:394148
rarga GeneProduct ncbigene:30606
cyp7a1a GeneProduct ncbigene:394148
LOC793309 GeneProduct ncbigene:793309
rargb GeneProduct ncbigene:100034753
cyp4t8 GeneProduct ncbigene:387527
cyp3a65 GeneProduct ncbigene:553969
cyp24a1 GeneProduct ncbigene:100004700
nr1h3 GeneProduct ncbigene:548341
cyp7a1a GeneProduct ncbigene:394148
nr1h4 GeneProduct ncbigene:436847 Farnesoid X-activated receptor
abcd3a GeneProduct ncbigene:406803