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Peroxisome proliferator-activated receptor-α

Systematic Nomenclature: NR1C1

Family: 1C. Peroxisome proliferator-activated receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
DNA Binding
Co-binding Partners
Main Co-regulators
Main Target Genes
Tissue Distribution
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
References
Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 468 22q12-q13.1 PPARA peroxisome proliferator-activated receptor alpha 55
Mouse 468 12 48.8 cM Ppara peroxisome proliferator activated receptor alpha 29
Rat 468 7q34 Ppara peroxisome proliferator activated receptor alpha 24
Previous and Unofficial Names
PPARα
hPPAR
PPARδ
NUC1
FAAR
PPAR
NR1C1
peroxisome proliferative activated receptor, alpha
PPAR-alpha
nuclear receptor subfamily 1 group C member 1
peroxisome proliferator activated receptor alpha
peroxisome proliferator-activated receptor alpha
PPARalpha
4933429D07Rik
AI118064
AW742785
Database Links
ChEMBL Target 163 (Hs), 10958 (Mm), 10959 (Rn)
DrugBank Target 80 (Hs)
Ensembl ENSG00000186951 (Hs), ENSMUSG00000022383 (Mm), ENSRNOG00000021463 (Rn)
Entrez Gene 5465 (Hs), 19013 (Mm), 25747 (Rn)
GeneCards PPARA (Hs)
GenitoUrinary Development Molecular Anatomy Project Ppara (Mm)
HomoloGene 21047 (Hs)
Human Protein Reference Database 01369 (Hs)
InterPro Q07869 (Hs), P23204 (Mm), P37230 (Rn)
KEGG Gene hsa:5465 (Hs), mmu:19013 (Mm), rno:25747 (Rn)
NURSA Receptor 1C1
OMIM 170998 (Hs)
PharmGKB Gene PA280 (Hs)
PhosphoSitePlus Q07869 (Hs), P23204 (Mm), P37230 (Rn)
RefSeq Nucleotide NM_001001928 (Hs), NM_011144 (Mm), NM_001113418 (Mm), NM_013196 (Rn)
RefSeq Protein NP_001001928 (Hs), NP_035274 (Mm), NP_037328 (Rn)
TreeFam ENSG00000186951 (Hs), ENSMUSG00000022383 (Mm), ENSRNOG00000021463 (Rn)
UniProt Q07869 (Hs), P23204 (Mm), P37230 (Rn)
1C. Peroxisome proliferator-activated receptors
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Peroxisome proliferator-activated receptor-α (ligand binding domain) - cocrytallised with agonist
PDB Id:  1K7L
Ligand:  GW409544
Resolution:  2.5Å
Species:  Human
References:  63
Search for other structures on the PDB
Search by keyword: Peroxisome proliferator-activated receptor-α Search by accession number: Q07869, P37230, P23204
Natural/Endogenous Ligand(s)
Comments: LTB4, fatty acids and eisosanoids are natural ligands
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
pterostilbene ? Agonist - -
MK-0767 Hs Agonist 6.8 – 7.64 pKd 11,49-50
8S-HETE Hs Agonist 7.0 pKd 17,69
GW2331 ? Agonist 6.8 pKd 37
GW7647 Hs Agonist 8.22 pEC50 3-4
GW9578 Hs Agonist 7.3 pEC50 3-5
imiglitazar Hs Agonist 7.17 pEC50 54
NS-220 Hs Agonist 6.73 pEC50 40
farglitazar Hs Agonist 6.35 pEC50 27,62
reglitazar Hs Agonist 5.72 pEC50 56
DRF 2519 Hs Agonist 5.0 pEC50 7
pristanic acid Hs Agonist 4.4 pEC50 75
bezafibrate Hs Agonist 4.3 pEC50 25,28
GW409544 Hs Agonist 8.7 pIC50 25,63
LY-518674 Hs Agonist 7.6 pIC50 65
TZD18 Hs Agonist 7.6 pIC50 23
LY-510929 Hs Agonist 7.55 pIC50 66
LTB4 ? Agonist 7.0 pIC50 9,39
oleoylethanolamide Hs Agonist 6.92 pIC50 19-20
LY-465608 Hs Agonist 6.8 pIC50 2,66
eicosatetranoic acid ? Agonist 6.7 pIC50 33-34
pirinixic acid Hs Agonist 6.22 pIC50 4,17
ragaglitazar Hs Agonist 6.0 pIC50 14
AD-5061 Hs Agonist 5.6 pIC50 53-54
fenofibric acid Hs Agonist 4.46 pIC50 28,43
clofibrate Hs Agonist 4.25 pIC50 25-26,62
View species-specific agonist tables
Agonist Comments
The following: pterostilbene,tetradecylglycidic acid and ortylthiopropionic acid (OTP) are also known agonists [8,52].

NB: In the cases where affinity values could not be found or were not measured, EC50 values for transactivation are mentioned. The ligands were gathered regarding the unit of the binding value and the ranking was made regarding each group of units.

Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GW6471 Hs Antagonist 6.6 pIC50 64
MK-886 Mm Antagonist 6.0 pIC50 32
View species-specific antagonist tables
DNA Binding
Structure:  Heterodimer, RXR partner
HRE core sequence:  5'-AACTAGGNCA A AGGTCA-3'
Response element:  DR1, DR2
DNA Binding Comments
binding on DR2 if the spacing sequence between the half-sites corresponds to that found in Rev-DR2 (AGGTCATCAGGTCA) in opposition to an alternative DR2 (AGGTCAGGAGGTCA) to which PPARalpha does not bind
Co-binding Partners
Name Interaction Effect Reference
RXR Physical, Functional DNA binding 37
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOR1 Co-repressor No No No 8,10,13
MED1 Co-activator No Yes Yes 74
NCOA1 Co-activator No Yes No 73
NCOA6 Co-activator No Yes Yes 6,72
HADHA Co-activator No No No 32
SMARCA2 Co-activator No No Yes 57
NRIP1 Co-repressor No Yes Yes 31,47,67
CREBBP Co-activator No Yes Yes There are contradicting results for ligand-dependency 12,71
CITED2 Co-activator No Yes Yes 58
NCOA3 Co-activator No No Yes 48
PPARGC1A Co-activator No No No 60
PPARGC1B Co-activator No No No 60
Main Target Genes
Name Species Effect Technique Comments References
CPTI: carnitine palmitoyl transferase I Human Activated Transient transfection 1,45,68
MCAD (medium chain acyl-coA dehydrogenase) Rat Activated Transient transfection 22
Acyl-CoA oxidase Rat Activated Transient transfection 44,59
G0/G1 switch gene 2 (G0S2) Mouse Activated 70
Fiat ( fasting induced adipose tissue factor) Mouse Activated 36
Bifunctional enzyme Mouse Activated Transient transfection 44
Slc27a1 Mouse Activated Transient transfection, EMSA FATP, fatty acid transport protein 18
Apolipoprotein A-II Mouse Activated Transient transfection, EMSA negative regulation of A-I 61
Liver fatty acid binding protein Mouse Activated 8,30
Tissue Distribution
Very active peroxisomal beta-oxidation tissues; liver, brown fat, kidney, heart, skeletal muscle, large intestine
Expression level:  High
Species:  Human
Technique:  Immunohistochemistry, Northern blot, Q-PCR, in situ hybridisation
References:  8
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0001544 abnormal cardiovascular system physiology PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0000188 abnormal circulating glucose level PMID: 11723064 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
B6.129S4-Ppara		 MGI:104740  MP:0000188 abnormal circulating glucose level PMID: 11723064 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0000184 abnormal circulating HDL cholesterol level PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0001560 abnormal circulating insulin level PMID: 11723064 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
B6.129S4-Ppara		 MGI:104740  MP:0001560 abnormal circulating insulin level PMID: 11723064 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0003457 abnormal circulating ketone body level PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0001216 abnormal epidermal layer morphology PMID: 12485431 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: C57BL/6		 MGI:104740  MP:0001216 abnormal epidermal layer morphology PMID: 10951268 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0001240 abnormal epidermis stratum corneum morphology PMID: 12485431 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0002078 abnormal glucose homeostasis PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0002078 abnormal glucose homeostasis PMID: 16054054 
Pparatm1Gonz|Tg(Ckm-Ppard)LEDpk Pparatm1Gonz/Pparatm1Gonz,Tg(Ckm-Ppard)LEDpk/0
involves: 129S4/SvJae * C57BL/6 * C57BL/6J * CBA		 MGI:104740  MGI:4429474  MP:0005291 abnormal glucose tolerance PMID: 16054054 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0000607 abnormal hepatocyte morphology PMID: 7539101 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: C57BL/6		 MGI:104740  MP:0002656 abnormal keratinocyte differentiation PMID: 10951268 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0004130 abnormal muscle cell glucose uptake PMID: 16054054 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0000278 abnormal myocardial fiber morphology PMID: 9739042 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0000278 abnormal myocardial fiber morphology PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0004215 abnormal myocardial fiber physiology PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0005329 abnormal myocardium layer morphology PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0006055 abnormal vascular endothelial cell morphology PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0003141 cardiac fibrosis PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0005330 cardiomyopathy PMID: 12552126 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0005330 cardiomyopathy PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0005560 decreased circulating glucose level PMID: 16054078 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0005439 decreased glycogen level PMID: 9739042 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: C57BL/6		 MGI:104740  MP:0009605 decreased keratohyalin granule number PMID: 10951268 
Ldlrtm1Her|Pparatm1Gonz Ldlrtm1Her/Ldlrtm1Her,Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6		 MGI:104740  MGI:96765  MP:0003961 decreased lean body mass PMID: 12847522 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0006264 decreased systemic arterial systolic blood pressure PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0002908 delayed wound healing PMID: 11514592 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0000599 enlarged liver PMID: 7539101 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0000599 enlarged liver PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0001853 heart inflammation PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0002628 hepatic steatosis PMID: 7539101  9739042 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0002628 hepatic steatosis PMID: 10377439  11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
B6.129S4-Ppara		 MGI:104740  MP:0002628 hepatic steatosis PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0000189 hypoglycemia PMID: 9739042 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0001596 hypotension PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0005292 improved glucose tolerance PMID: 16054054 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0001260 increased body weight PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0005178 increased circulating cholesterol level PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0005178 increased circulating cholesterol level PMID: 16054078 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0001554 increased circulating free fatty acid level PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0001554 increased circulating free fatty acid level PMID: 16054078 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0002079 increased circulating insulin level PMID: 16054078 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
B6.129S4-Ppara		 MGI:104740  MP:0001552 increased circulating triglyceride level PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0009285 increased gonadal fat pad weight PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
B6.129S4-Ppara		 MGI:104740  MP:0009285 increased gonadal fat pad weight PMID: 11495927 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0002891 increased insulin sensitivity PMID: 16054054 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6N		 MGI:104740  MP:0009763 increased sensitivity to induced morbidity/mortality PMID: 9739042 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0009763 increased sensitivity to induced morbidity/mortality PMID: 10377439 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0005658 increased susceptibility to diet-induced obesity PMID: 16054054 
Ldlrtm1Her|Pparatm1Gonz Ldlrtm1Her/Ldlrtm1Her,Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6		 MGI:104740  MGI:96765  MP:0010024 increased total body fat amount PMID: 12847522 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae * C57BL/6J		 MGI:104740  MP:0005317 increased triglyceride level PMID: 16054054 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
129S4/SvJae-Ppara		 MGI:104740  MP:0005331 insulin resistance PMID: 11723064 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0004566 myocardial fiber degeneration PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: 129S4/SvJae		 MGI:104740  MP:0006085 myocardial necrosis PMID: 10801788 
Pparatm1Gonz Pparatm1Gonz/Pparatm1Gonz
involves: C57BL/6		 MGI:104740  MP:0009598 thin epidermis stratum granulosum PMID: 10951268 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Arteriosclerosis
References:  35,38
Mutations not determined
Gene Expression and Pathophysiology
PPARα KO
Tissue or cell type:  in vivo
Pathophysiology:  Hypothermia and hypoglycemia upon fasting, reduced insulin resistance, prolonged inflammatory reaction, transient delay in skin healing, resistance to fibrate induced cancer
Species:  Mouse
Technique:  in vivo Knock Out
References:  9,21,36,41-42,46,52
Cardio-specific PPAR α overexpression.
Tissue or cell type:  Cardiac vascular
Pathophysiology:  Cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, reduced heart function.
Species:  Mouse
Technique:  Transgenic mouse produced by microinjection of MHC-PPAR construct into fertilized one-cell C57BL/6CBA/J embryos.
References:  16,51
PPARα delta 13:-dominant negative mutant
Tissue or cell type:  in vivo
Pathophysiology:  Transient impaired wound healing ; inflammatory phase impaired
Species:  Mouse
Technique:  in vivo generation of transgenic mouse
References:  45
PPARalpha overexpression in muscle
Tissue or cell type:  Myocytes
Pathophysiology:  Development of glucose intolerance, increased fatty acid oxidation rates, reduced AMP-activated protein kinase activity, reduced insulin-stimulated glucose uptake, repression of GLUT4 gene
Species:  Mouse
Technique:  in vivo generation of transgenic mouse
References:  15

REFERENCES

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1C. Peroxisome proliferator-activated receptors: Peroxisome proliferator-activated receptor-α. Last modified on 01/04/2013. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=593.


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