Nuclear Receptors in Lipid Metabolism and Toxicity (Bos taurus)

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DIETXenobioticsDIETGene expressionFatty AcidsCYP3A4Retinoic acidCholesterolSteroidsMIR33AABCG5CYP7A1VDRRARACYP4B1Acetyl CoAIsoprenoidsABCC3LanosterolBile AcidsCYP2C9ABCG1CYP2E1ABCA1NR1I2CYP2B6RARGABCA1CYP2C9CYP3A4CYP2B6ABCC2NR1H3RARBCYP7A1ABCB11CYP27B1CYP7A1CYP2C9MIR33BCYP3A4ABCD2abcg6PPARDCYP8B1ABCB1CYP24A1ABCB1aCYP4A11CYP1A27-DehydroCholesterolNR1H4ABCB4PPARAABCA1ABCD31,25-Dihydroxy-Vitamins D3NR1I3CYP26A1OxysterolPPARGMIR33AMIR33BMIR33AMIR33B


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.


This pathway was inferred from Homo sapiens pathway WP299(r45336) with a 64% conversion rate.

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107077view14:16, 17 September 2019MaintBotChEBI identifier normalization
105942view11:47, 16 August 2019MaintBotHMDB identifier normalization
96300view18:03, 7 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
80762view15:25, 30 June 2015Mkutmonhomology conversion
78597view14:51, 7 January 2015MaintBotadded missing graphIds
70173view00:42, 13 July 2013AlexanderPicoModified title
67542view11:23, 26 June 2013DdiglesOntology Term : 'lipid metabolic pathway' added !
63398view00:04, 10 May 2013MaintBotUpdated to 2013 gpml schema
48130view05:49, 9 May 2012MaintBotUpdating from human to fix xref duplication
40571view19:32, 1 March 2011MaintBotRemoved redundant pathway information and comments
35680view22:50, 12 February 2010KhanspersDescription
35678view22:49, 12 February 2010KhanspersModified description
33809view00:20, 9 December 2009MaintBotAutomatic update of empty xrefs
33625view10:03, 1 December 2009MaintBotRemoved group label
30550view21:59, 29 July 2009MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
1,25-Dihydroxy-Vitamins D3Metabolite
7-DehydroCholesterolMetabolite434-16-2 (CAS)
ABCA1GeneProduct535379 (Entrez Gene)
ABCB11GeneProduct531150 (Entrez Gene)
ABCB1GeneProduct281585 (Entrez Gene)
ABCB4GeneProduct100336913 (Entrez Gene)
ABCC2GeneProduct520925 (Entrez Gene)
ABCC3GeneProduct533151 (Entrez Gene)
ABCD3GeneProduct526059 (Entrez Gene)
ABCG1GeneProduct510745 (Entrez Gene)
ABCG5GeneProduct515536 (Entrez Gene)
Acetyl CoAMetabolite72-89-9 (CAS)
Bile AcidsMetabolite3098 (ChEBI)
CYP1A2GeneProduct503552 (Entrez Gene)
CYP24A1GeneProduct540080 (Entrez Gene)
CYP26A1GeneProduct539047 (Entrez Gene)
CYP27B1GeneProduct539630 (Entrez Gene)
CYP2B6GeneProduct504769 (Entrez Gene)
CYP2E1GeneProduct282213 (Entrez Gene)
CYP4B1GeneProduct540149 (Entrez Gene)
CYP7A1GeneProduct510507 (Entrez Gene)
CholesterolMetabolite57-88-5 (CAS)
Fatty AcidsMetabolite35366 (ChEBI)
IsoprenoidsMetabolite24913 (ChEBI)
LanosterolMetabolite6374 (ChEBI)
NR1H3GeneProduct507176 (Entrez Gene)
NR1H4GeneProduct540528 (Entrez Gene) Farnesoid X-activated receptor
NR1I2GeneProduct493713 (Entrez Gene)
NR1I3GeneProduct493711 (Entrez Gene)
PPARAGeneProduct281992 (Entrez Gene)
PPARDGeneProduct353106 (Entrez Gene)
PPARGGeneProduct281993 (Entrez Gene)
RARAGeneProduct534280 (Entrez Gene)
RARGGeneProduct540425 (Entrez Gene)
Retinoic acidMetaboliteHMDB01852 (HMDB)
VDRGeneProduct533656 (Entrez Gene)

Annotated Interactions

No annotated interactions
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