Nuclear receptors in lipid metabolism and toxicity (WP431)

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.
last edited

Authors

S.Burel, MaintBot, Khanspers, Thomas, Ddigles, Mkutmon, and Egonw

Cited In

Organism

Mus musculus

Communities

Annotations

Pathway Ontology: lipid metabolic pathway

Participants

Label Type Compact Identifier
Fatty Acids Metabolite chebi:35366
Abca1 GeneProduct ncbigene:11303
CYP3A4 GeneProduct None
Ppara GeneProduct ncbigene:19013
Abcc2 GeneProduct ncbigene:12780
Pparg GeneProduct ncbigene:19016
Nr1i2 GeneProduct ncbigene:18171
Abcb11 GeneProduct ncbigene:27413
Rara GeneProduct ncbigene:19401
Cyp8b1 GeneProduct ncbigene:13124
Cyp1a2 GeneProduct ncbigene:13077
Abcg5 GeneProduct ncbigene:27409
Steroids Metabolite None
Abcg1 GeneProduct ncbigene:11307
Cholesterol Metabolite hmdb:HMDB0000067
7-Dehydrocholesterol Metabolite hmdb:HMDB0000032
CYP2C9 GeneProduct None
Abca1 GeneProduct ncbigene:11303
CYP3A4 GeneProduct None
1,25-Dihydroxyvitamin D3s Metabolite hmdb:HMDB0000969
Cyp26a1 GeneProduct ncbigene:13082
Nr1i3 GeneProduct ncbigene:12355
Vdr GeneProduct ncbigene:22337
Abcc3 GeneProduct ncbigene:76408
CYP4A11 GeneProduct None
Cyp2b10 GeneProduct ncbigene:13088
Cyp7a1 GeneProduct ncbigene:13122
Bile Acids Metabolite chebi:3098
Rarb GeneProduct ncbigene:218772
Cyp7a1 GeneProduct ncbigene:13122
Abca1 GeneProduct ncbigene:11303
Retinoic acid Metabolite hmdb:HMDB0001852
Acetyl-CoA Metabolite hmdb:HMDB0001206
Cyp27b1 GeneProduct ncbigene:13115
Cyp2b10 GeneProduct ncbigene:13088
Rarg GeneProduct ncbigene:19411
Cyp4b1 GeneProduct ncbigene:13120
CYP3A4 GeneProduct None
Abcb4 GeneProduct ncbigene:18670
abcg6 GeneProduct None
Cyp24a1 GeneProduct ncbigene:13081
Nr1h3 GeneProduct ncbigene:22259
Cyp7a1 GeneProduct ncbigene:13122
Abcb1a GeneProduct ncbigene:18671
Nr1h4 GeneProduct ncbigene:20186
Cyp2e1 GeneProduct ncbigene:13106
Lanosterol Metabolite chebi:16521
Oxysterol Metabolite None
CYP2C9 GeneProduct None
Abcd2 GeneProduct ncbigene:26874
Ppard GeneProduct ncbigene:19015
Abcd3 GeneProduct ncbigene:19299
Abcb1a GeneProduct ncbigene:18671
CYP2C9 GeneProduct None
Isoprenoids Metabolite chebi:24913

References