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peroxisome proliferator-activated receptor alpha; PPAR-alpha; nuclear receptor subfamily 1 group C member 1 (PPARA, NR1C1, PPAR)
Function:
1) activated by fatty acids & peroxisome proliferators
2) binds to DNA as heterodimer with RXR
3) physiologic roles: [1]
a) lipid metabolism
1] inhibition of adipocyte differentiation
2] upregulation of enzymes that regulate lipolysis & fatty acid oxidation in adipocytes
b) down-regulation of inflammation
4) forms heterodimers with retinoic acid receptor-X (RXR); the PPAR-alpha/RXR heterodimer binds to the PPRE enhancer element.
5) activated PPAR-alpha/RXR:
a) inhibits:
1] AP1 via binding to jun
2] NF-kappa B via binding to p65
b) may compete other nuclear receptors for RXRE enhancer elements (improper fit may bind without activation)
c) induces peroxisome proliferation
d) induces beta-oxidation of fatty acids
6) endogenous ligands (activators)
a) saturated fatty acids
1] palmitic acid [16:0] (3+)
2] stearic acid [18:0] (3+)
b) monounsaturated fatty acids
1] palmitoleic acid [16:1] (3+)
2] oleic acid [18:1] (3+)
3] elaidic acid [20:1] (2+)
c) polyunsaturated fatty acids
1] linoleic acid [18:2, n-6] (3+)
2] alpha-linolenic acid [18:3, n-3] (3+)
3] gamma-linolenic acid [18:3, n-6] (3+)
4] dihomo-gamma-linolenic acid [20:3, n-6] (3+)
5] arachidonic acid [20:4, n-6] (3+)
6] eicosapentaenoic acid [22:5, n-3] (3+)
7] docosahexaenoic acid [22:6, n-3] (2+)
d) eicosanoids
1] PGA1 (+)
2] PGA2 (+)
3] PGD1 (2+)
4] PGD2 (2+)
5] PGJ2 (+)
6] 15-deoxy-delta 12,14-PGJ2 (+)
7] 8(S)-HETE (3+)
8] 8-HEPE (2+)
9] LTB4 (+/-)
7) coactivators include:
a) PPAR-binding protein
b) steroid coactivator-1 (SRC-1) (may be insignificant)
8) corepressors include:
a) RXR-interacting protein 13 (nuclear receptor corepressor)
b) SMRT/TRAC c ) RIP140
9) other interactions:
a) dUTPase prevents PPAR-RXR heterodimerization
b) HMG CoA synthase
- not strictly coactivator but increases activity of PPAR-alpha
c) c-jun inhibits activation of PPAR-alpha/RXR (reciprocal inhibition)
* uncertain as to identity of these proteins
Expression:
1) liver, intestine (4+)
2) kidney (2+)
3) spleen (1+) [1]
Pathology:
- PPAR-alpha essential for hepatocarcinogenicity of peroxisome proliferators (mechanism unknown)
Pharmacology:
Exogenous agonists: (peroxisome proliferators) [1]
1) hypolipidemic drugs
a) WY-14-643 (3+)
b) clofibrate (2+)
c) ciprofibrate (2+)
d) gemfibrozil (2+)
e) nafenopin (2+)
f) GW2331 (3+)
g) bezafibrate (1+)
2) non-steroidal anti-inflammatory drugs (NSAIDs)
a) indomethacin (1+)
b) ibuprofen (1+)
c) fenoprofen (2+)
3) other
a) monoethylhexyl phthalate (3+)
b) trichloroacetic acid (1+)
c) eicosatetraynoic acid (ETYA) (3+)
d) LTB4 antagonists
1] MK-571 (2+)
2] LY-171883 (2+)
Interactions
molecular events
Related
hydroxymethylglutaryl [HMG] CoA synthase
peroxisome proliferator response element (PPRE)
retinoid X receptor (RXR)
General
peroxisome proliferator-activated receptor (PPAR)
Properties
SIZE: entity length = 468 aa
MW = 52 kD
COMPARTMENT: cell nucleus
MOTIF: DNA-binding motif
SITE: 99-173
MOTIF: Zn finger C4-type
SITE: 102-122
EFFECTOR-BOUND: Zn+2
Zn finger C4-type
SITE: 139-161
EFFECTOR-BOUND: Zn+2
binding site
SITE: 280-468
FOR-BINDING-OF: ligand
MOTIF: binding site
SITE: 280-280
FOR-BINDING-OF: agonist
binding site
SITE: 314-314
FOR-BINDING-OF: agonist
binding site
SITE: 440-440
FOR-BINDING-OF: agonist
binding site
SITE: 464-464
FOR-BINDING-OF: agonist
Database Correlations
OMIM 170998
MORBIDMAP 170998
UniProt Q07869
PFAM correlations
Kegg hsa:5465
References
- Corton JC, Anderson SP, Stauber A.
Central role of peroxisome proliferator-activated receptors
in the actions of peroxisome proliferators.
Annu Rev Pharmacol Toxicol. 2000;40:491-518. Review.
PMID: 10836145
- UniProt :accession Q07869