Nuclear receptors in lipid metabolism and toxicity (WP863)

Pan troglodytes

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.


Kristina Hanspers , Daniela Digles , Egon Willighagen , and Lauren J. Dupuis


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Pan troglodytes



Pathway Ontology

lipid metabolic pathway


Label Type Compact URI Comment
Fatty Acids Metabolite chebi:35366
Cholesterol Metabolite cas:57-88-5
7-DehydroCholesterol Metabolite cas:434-16-2
Bile Acids Metabolite chebi:3098
Retinoic acid Metabolite hmdb:HMDB0001852
Acetyl CoA Metabolite cas:72-89-9
Lanosterol Metabolite chebi:16521
Isoprenoids Metabolite chebi:24913
ABCA1 GeneProduct ncbigene:464630
CYP3A4 GeneProduct ncbigene:463582
PPARA GeneProduct ncbigene:458910
PPARG GeneProduct ncbigene:460178
NR1I2 GeneProduct ncbigene:745458
ABCB11 GeneProduct ncbigene:470717
RARA GeneProduct ncbigene:454647
LOC736962 GeneProduct ncbigene:736962
LOC735881 GeneProduct ncbigene:735881
LOC459190 GeneProduct ncbigene:459190
ABCG1 GeneProduct ncbigene:458577
LOC100616515 GeneProduct ncbigene:100616515
ABCA1 GeneProduct ncbigene:464630
CYP3A4 GeneProduct ncbigene:463582
LOC450614 GeneProduct ncbigene:450614
NR1I3 GeneProduct ncbigene:458014
LOC451858 GeneProduct ncbigene:451858
ABCC3 GeneProduct ncbigene:747938
LOC739864 GeneProduct ncbigene:739864
LOC456052 GeneProduct ncbigene:456052
CYP7A1 GeneProduct ncbigene:464191
RARB GeneProduct ncbigene:745516
CYP7A1 GeneProduct ncbigene:464191
ABCA1 GeneProduct ncbigene:464630
CYP27B1 GeneProduct ncbigene:452027
LOC456052 GeneProduct ncbigene:456052
RARG GeneProduct ncbigene:451935
LOC456557 GeneProduct ncbigene:456557
CYP3A4 GeneProduct ncbigene:463582
ABCB4 GeneProduct ncbigene:748364
LOC746729 GeneProduct ncbigene:746729
NR1H3 GeneProduct ncbigene:466507
CYP7A1 GeneProduct ncbigene:464191
NR1H4 GeneProduct ncbigene:452162 Farnesoid X-activated receptor
LOC450857 GeneProduct ncbigene:450857
LOC100616515 GeneProduct ncbigene:100616515
ABCD2 GeneProduct ncbigene:466952
PPARD GeneProduct ncbigene:463188
ABCB1 GeneProduct ncbigene:463516
LOC100616515 GeneProduct ncbigene:100616515