Nuclear receptors in lipid metabolism and toxicity (Danio rerio)

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XenobioticsDIETDIETGene expressionOxysterolrargaABCD2ABCB1aabcd3aABCB1CYP2C9Bile AcidsCYP4A11ABCC3nr1h3Lanosterol7-DehydroCholesterolCYP2E1PPARDLOC793309MIR33ARetinoic acidCYP1A2NR1I3rargbIsoprenoidsCYP2B6CYP8B1Acetyl CoAcyp7a1aCYP2B6MIR33B1,25-Dihydroxy-Vitamins D3ABCA1ABCA1Steroidscyp24a1ABCB4CYP2C9abcg6abcb11bABCA1ppargcyp26a1Cholesterolcyp3a65abcg1Fatty Acidscyp3a65cyp4t8cyp7a1acyp3a65abcg5abcc2RARAnr1i2CYP2C9VDRcyp7a1anr1h4PPARAMIR33AMIR33BMIR33AMIR33B


Description

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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP299(r45336) with a 42% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
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

DataNodes

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NameTypeDatabase referenceComment
1,25-Dihydroxy-Vitamins D3Metabolite
7-DehydroCholesterolMetabolite434-16-2 (CAS)
ABCA1GeneProduct
ABCB1GeneProduct
ABCB1aGeneProduct
ABCB4GeneProduct
ABCC3GeneProduct
ABCD2GeneProduct
Acetyl CoAMetabolite72-89-9 (CAS)
Bile AcidsMetaboliteCHEBI:3098 (ChEBI)
CYP1A2GeneProduct
CYP2B6GeneProduct
CYP2C9GeneProduct
CYP2E1GeneProduct
CYP4A11GeneProduct
CYP8B1GeneProduct
CholesterolMetabolite57-88-5 (CAS)
Fatty AcidsMetaboliteCHEBI:35366 (ChEBI)
IsoprenoidsMetaboliteCHEBI:24913 (ChEBI)
LOC793309GeneProduct793309 (Entrez Gene)
LanosterolMetaboliteCHEBI:16521 (ChEBI)
MIR33AGeneProduct
MIR33BGeneProduct
NR1I3GeneProduct
OxysterolMetabolite
PPARAGeneProduct
PPARDGeneProduct
RARAGeneProduct
Retinoic acidMetaboliteHMDB0001852 (HMDB)
SteroidsMetabolite
VDRGeneProduct
abcb11bGeneProduct571189 (Entrez Gene)
abcc2GeneProduct393561 (Entrez Gene)
abcd3aGeneProduct406803 (Entrez Gene)
abcg1GeneProduct556979 (Entrez Gene)
abcg5GeneProduct557317 (Entrez Gene)
abcg6GeneProduct
cyp24a1GeneProduct100004700 (Entrez Gene)
cyp26a1GeneProduct30381 (Entrez Gene)
cyp3a65GeneProduct553969 (Entrez Gene)
cyp4t8GeneProduct387527 (Entrez Gene)
cyp7a1aGeneProduct394148 (Entrez Gene)
nr1h3GeneProduct548341 (Entrez Gene)
nr1h4GeneProduct436847 (Entrez Gene) Farnesoid X-activated receptor
nr1i2GeneProduct565875 (Entrez Gene)
ppargGeneProduct557037 (Entrez Gene)
rargaGeneProduct30606 (Entrez Gene)
rargbGeneProduct100034753 (Entrez Gene)

Annotated Interactions

No annotated interactions
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