Nuclear receptors in lipid metabolism and toxicity (Pan troglodytes)

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XenobioticsDIETDIETGene expressionLanosterolBile AcidsLOC100616515CYP7A1PPARDABCD3MIR33ACYP7A1ABCC3LOC451858LOC746729LOC450857MIR33BNR1H4ABCD2Acetyl CoA7-DehydroCholesterolFatty AcidsABCA1LOC736962LOC450614LOC456052LOC100616515LOC739864RARARetinoic acidLOC456052IsoprenoidsCYP27B1CholesterolCYP3A4CYP7A1LOC459190abcg6CYP3A4ABCB1ABCB4NR1I2LOC100616515ABCC21,25-Dihydroxy-Vitamins D3ABCG1LOC456557SteroidsABCA1RARGNR1H3ABCA1LOC735881PPARAABCB11PPARGOxysterolNR1I3RARBABCB1aCYP3A4MIR33AMIR33BMIR33AMIR33B


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 80% conversion rate.

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109476view11:12, 18 March 2020L DupuisFixed interactions
107221view14:31, 17 September 2019MaintBotChEBI identifier normalization
106918view13:39, 17 September 2019MaintBotHMDB identifier normalization
96306view18:34, 7 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
78374view10:22, 7 January 2015MaintBotadded missing graphIds
69219view18:32, 8 July 2013MaintBotUpdated to 2013 gpml schema
67541view11:23, 26 June 2013DdiglesOntology Term : 'lipid metabolic pathway' added !
48164view20:22, 9 May 2012MaintBotUpdating from human to fix xrefs
41521view01:56, 2 March 2011MaintBotRemoved redundant pathway information and comments
35693view23:01, 12 February 2010KhanspersDescription
35692view23:00, 12 February 2010KhanspersModified description
34260view21:50, 9 December 2009MaintBotAutomatic update of empty xrefs
33529view09:34, 1 December 2009MaintBotRemoved group label
30432view21:20, 29 July 2009MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
1,25-Dihydroxy-Vitamins D3Metabolite
7-DehydroCholesterolMetabolite434-16-2 (CAS)
ABCA1GeneProduct464630 (Entrez Gene)
ABCB11GeneProduct470717 (Entrez Gene)
ABCB1GeneProduct463516 (Entrez Gene)
ABCB4GeneProduct748364 (Entrez Gene)
ABCC3GeneProduct747938 (Entrez Gene)
ABCD2GeneProduct466952 (Entrez Gene)
ABCG1GeneProduct458577 (Entrez Gene)
Acetyl CoAMetabolite72-89-9 (CAS)
Bile AcidsMetaboliteCHEBI:3098 (ChEBI)
CYP27B1GeneProduct452027 (Entrez Gene)
CYP3A4GeneProduct463582 (Entrez Gene)
CYP7A1GeneProduct464191 (Entrez Gene)
CholesterolMetabolite57-88-5 (CAS)
Fatty AcidsMetaboliteCHEBI:35366 (ChEBI)
IsoprenoidsMetaboliteCHEBI:24913 (ChEBI)
LOC100616515GeneProduct100616515 (Entrez Gene)
LOC450614GeneProduct450614 (Entrez Gene)
LOC450857GeneProduct450857 (Entrez Gene)
LOC451858GeneProduct451858 (Entrez Gene)
LOC456052GeneProduct456052 (Entrez Gene)
LOC456557GeneProduct456557 (Entrez Gene)
LOC459190GeneProduct459190 (Entrez Gene)
LOC735881GeneProduct735881 (Entrez Gene)
LOC736962GeneProduct736962 (Entrez Gene)
LOC739864GeneProduct739864 (Entrez Gene)
LOC746729GeneProduct746729 (Entrez Gene)
LanosterolMetaboliteCHEBI:16521 (ChEBI)
NR1H3GeneProduct466507 (Entrez Gene)
NR1H4GeneProduct452162 (Entrez Gene) Farnesoid X-activated receptor
NR1I2GeneProduct745458 (Entrez Gene)
NR1I3GeneProduct458014 (Entrez Gene)
PPARAGeneProduct458910 (Entrez Gene)
PPARDGeneProduct463188 (Entrez Gene)
PPARGGeneProduct460178 (Entrez Gene)
RARAGeneProduct454647 (Entrez Gene)
RARBGeneProduct745516 (Entrez Gene)
RARGGeneProduct451935 (Entrez Gene)
Retinoic acidMetaboliteHMDB0001852 (HMDB)

Annotated Interactions

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