Nuclear receptors in lipid metabolism and toxicity (WP299)

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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP299 CPTAC Assay Portal]
last edited

Authors

S.Burel, MaintBot, Thomas, Khanspers, Samuel Sklar, AlexanderPico, Egonw, Mkutmon, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: lipid metabolic pathway

Participants

Label Type Compact Identifier
Xenobiotics Metabolite chebi:35703
Fatty Acids Metabolite chebi:35366
ABCA1 GeneProduct ncbigene:19
CYP3A4 GeneProduct ncbigene:1576
PPARA GeneProduct ncbigene:5465
ABCC2 GeneProduct ncbigene:1244
PPARG GeneProduct ncbigene:5468
NR1I2 GeneProduct ncbigene:8856
ABCB11 GeneProduct ncbigene:8647
RARA GeneProduct ncbigene:5914
CYP8B1 GeneProduct ncbigene:1582
CYP1A2 GeneProduct ncbigene:1544
ABCG5 GeneProduct ncbigene:64240
Steroids Metabolite chebi:35341
ABCG1 GeneProduct ncbigene:9619
Cholesterol Metabolite cas:57-88-5
MIR33B GeneProduct ensembl:ENSG00000207839
7-DehydroCholesterol Metabolite cas:434-16-2
MIR33A GeneProduct ensembl:ENSG00000207932
CYP2C9 GeneProduct ncbigene:1559
ABCA1 GeneProduct ncbigene:19
CYP3A4 GeneProduct ncbigene:1576
1,25-Dihydroxy-Vitamins D3 Metabolite chebi:17823
CYP26A1 GeneProduct ncbigene:1592
NR1I3 GeneProduct ncbigene:9970
VDR GeneProduct ncbigene:7421
ABCC3 GeneProduct ncbigene:8714
CYP4A11 GeneProduct ncbigene:1579
CYP2B6 GeneProduct ncbigene:1555
CYP7A1 GeneProduct ncbigene:1581
Bile Acids Metabolite chebi:3098
RARB GeneProduct ncbigene:5915
CYP7A1 GeneProduct ncbigene:1581
ABCA1 GeneProduct ncbigene:19
Retinoic acid Metabolite hmdb:HMDB0001852
Acetyl CoA Metabolite cas:72-89-9
CYP27B1 GeneProduct ncbigene:1594
CYP2B6 GeneProduct ncbigene:1555
RARG GeneProduct ncbigene:5916
CYP4B1 GeneProduct ncbigene:1580
CYP3A4 GeneProduct ncbigene:1576
ABCB4 GeneProduct ncbigene:5244
abcg6 GeneProduct None
CYP24A1 GeneProduct ncbigene:1591
NR1H3 GeneProduct ncbigene:10062
CYP7A1 GeneProduct ncbigene:1581
ABCB1a GeneProduct None
NR1H4 GeneProduct ncbigene:9971
CYP2E1 GeneProduct ncbigene:1571
Lanosterol Metabolite chebi:16521
Oxysterol Metabolite chebi:53030
CYP2C9 GeneProduct ncbigene:1559
ABCD2 GeneProduct ncbigene:225
PPARD GeneProduct ncbigene:5467
ABCD3 GeneProduct ncbigene:5825
ABCB1 GeneProduct ncbigene:5243
CYP2C9 GeneProduct ncbigene:1559
Isoprenoids Metabolite chebi:24913
MIR33A GeneProduct ensembl:ENSG00000207932
MIR33B GeneProduct ensembl:ENSG00000207839
MIR33A GeneProduct ensembl:ENSG00000207932
MIR33B GeneProduct ensembl:ENSG00000207839

References