Nuclear receptors in lipid metabolism and toxicity (Gallus gallus)

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Gene expressionDIETXenobioticsDIETABCC2CYP7A1Fatty AcidsABCG5ABCA1ABCA1SteroidsPPARGRARANR1H3ABCB4CYP3A80RARBCYP8BCYP3A80OxysterolCYP1A2CYP7A1CYP2E1VDRABCB11RARGABCD2abcg6NR1I3LanosterolCYP24A1NR1I2CYP2C9Bile AcidsCYP27B1NR1H4ABCG1CYP4B1IsoprenoidsABCB1CYP2C91,25-Dihydroxy-Vitamins D3Retinoic acidABCA1CYP2B6CYP7A1ABCD3CYP2B6PPARACholesterolPPARDAcetyl CoAABCC3CYP2C9CYP26A1CYP3A80CYP4B1ABCB1A7-DehydroCholesterol


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.


GenMAPP remarks 
Converted to human by
This pathway was inferred from Homo sapiens pathway WP299(r21309) with a 57% conversion rate.

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107105view14:18, 17 September 2019MaintBotChEBI identifier normalization
106108view12:01, 16 August 2019MaintBotHMDB identifier normalization
96343view09:27, 9 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
89869view12:38, 6 October 2016MkutmonModified description
89868view12:37, 6 October 2016MkutmonModified description
89867view12:35, 6 October 2016MkutmonModified description
74225view15:10, 8 April 2014EgonwRemoved a data source where no ID was given.
72374view13:03, 13 November 2013EgonwRemoved a few data sources where no identifier was given.
69991view22:17, 11 July 2013MaintBotupdated to 2013 schema
67540view11:23, 26 June 2013DdiglesOntology Term : 'lipid metabolic pathway' added !
47791view16:29, 6 April 2012Khanspersupdated xref
41023view22:57, 1 March 2011MaintBotRemoved redundant pathway information and comments
35690view22:58, 12 February 2010KhanspersDescription
35688view22:57, 12 February 2010KhanspersModified description
33944view18:15, 9 December 2009MaintBotAutomatic update of empty xrefs
33440view14:57, 30 November 2009MaintBotRemoved group label
30324view20:44, 29 July 2009MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
1,25-Dihydroxy-Vitamins D3Metabolite
ABCA1GeneProduct373945 (Entrez Gene)
ABCB11GeneProduct424170 (Entrez Gene)
ABCB1GeneProduct420534 (Entrez Gene)
ABCC2GeneProduct423828 (Entrez Gene)
ABCC3GeneProduct422099 (Entrez Gene)
ABCD2GeneProduct417694 (Entrez Gene)
ABCD3GeneProduct424487 (Entrez Gene)
ABCG1GeneProduct418533 (Entrez Gene)
ABCG5GeneProduct421401 (Entrez Gene)
Acetyl CoAMetabolite
Bile AcidsMetaboliteCHEBI:3098 (ChEBI)
CYP1A2GeneProduct414856 (Entrez Gene)
CYP24A1GeneProduct395827 (Entrez Gene)
CYP26A1GeneProduct408183 (Entrez Gene)
CYP3A80GeneProduct416477 (Entrez Gene)
CYP4B1GeneProduct424618 (Entrez Gene)
CYP7A1GeneProduct414834 (Entrez Gene)
CYP8BGeneProduct425055 (Entrez Gene)
Fatty AcidsMetaboliteCHEBI:35366 (ChEBI)
IsoprenoidsMetaboliteCHEBI:24913 (ChEBI)
LanosterolMetaboliteCHEBI:16521 (ChEBI)
NR1H3GeneProduct395221 (Entrez Gene)
NR1H4GeneProduct373902 (Entrez Gene) Farnesoid X-activated receptor
NR1I3GeneProduct395439 (Entrez Gene)
PPARAGeneProduct374120 (Entrez Gene)
PPARDGeneProduct395479 (Entrez Gene)
PPARGGeneProduct373928 (Entrez Gene)
RARAGeneProduct395213 (Entrez Gene)
RARBGeneProduct396266 (Entrez Gene)
Retinoic acidMetaboliteHMDB0001852 (HMDB)
VDRGeneProduct395988 (Entrez Gene)

Annotated Interactions

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