Nuclear receptors in lipid metabolism and toxicity (Danio rerio)

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DIETDIETXenobioticsGene expressionzgc:63920cyp3a657-DehydroCholesterolABCB1Fatty AcidsrargbABCC3CholesterolCYP2C9cyp3a65tpteNR1I3abcc2CYP2C9CYP2B6nr1h4cyp24a1lCYP2C9vdrbLOC791965Lanosterolppargabca1aRetinoic acidabca1aABCB11CYP4B1ABCD2abcg5Acetyl CoApparabcyp3a65CYP27B1CYP1A2nr1h31,25-Dihydroxy-Vitamins D3IsoprenoidsRARABile Acidsnr1i2zgc:63920cyp26a1rargaabca1aSteroidsOxysterolCYP2E1zgc:162197abcg6abcd3appardbzgc:63920CYP8B1CYP2B6ABCB4


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 drug’s subsequentconversion to acetyl-p-benzoquinone imine (NAPQI) by CYP1A2, CYP2E1 and CYP3A.


GenMAPP remarks 
Converted to human by
This pathway was inferred from Homo sapiens pathway WP299(r21309) with a 55% conversion rate.

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107094view14:17, 17 September 2019MaintBotChEBI identifier normalization
106067view11:58, 16 August 2019MaintBotHMDB identifier normalization
96394view09:54, 12 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
78352view09:34, 7 January 2015MaintBotadded missing graphIds
68630view04:42, 6 July 2013MaintBotUpdated to 2013 gpml schema
67537view11:22, 26 June 2013DdiglesOntology Term : 'lipid metabolic pathway' added !
47921view22:15, 18 April 2012KhanspersUpdating from human to fix xref duplication
40796view22:16, 1 March 2011MaintBotRemoved redundant pathway information and comments
35687view22:56, 12 February 2010KhanspersDescription
35685view22:55, 12 February 2010KhanspersModified description
34185view21:23, 9 December 2009MaintBotAutomatic update of empty xrefs
31917view12:51, 14 August 2009MaintBotFixed group labels
31036view01:16, 30 July 2009MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
1,25-Dihydroxy-Vitamins D3Metabolite
Acetyl CoAMetabolite
Bile AcidsMetabolite3098 (ChEBI)
Fatty AcidsMetabolite35366 (ChEBI)
IsoprenoidsMetabolite24913 (ChEBI)
LOC791965GeneProduct791965 (Entrez Gene)
LanosterolMetabolite6374 (ChEBI)
Retinoic acidMetaboliteHMDB01852 (HMDB)
abca1aGeneProduct558924 (Entrez Gene)
abcc2GeneProduct393561 (Entrez Gene)
abcd3aGeneProduct406803 (Entrez Gene)
abcg5GeneProduct557317 (Entrez Gene)
cyp24a1lGeneProduct100004700 (Entrez Gene)
cyp26a1GeneProduct30381 (Entrez Gene)
cyp3a65GeneProduct553969 (Entrez Gene)
nr1h3GeneProduct548341 (Entrez Gene)
nr1h4GeneProduct436847 (Entrez Gene) Farnesoid X-activated receptor
nr1i2GeneProduct565875 (Entrez Gene)
pparabGeneProduct557714 (Entrez Gene)
ppardbGeneProduct30754 (Entrez Gene)
ppargGeneProduct557037 (Entrez Gene)
rargaGeneProduct30606 (Entrez Gene)
rargbGeneProduct100034753 (Entrez Gene)
tpteGeneProduct327292 (Entrez Gene)
vdrbGeneProduct564511 (Entrez Gene)
zgc:162197GeneProduct556979 (Entrez Gene)
zgc:63920GeneProduct394148 (Entrez Gene)

Annotated Interactions

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