Peroxisome proliferator-activated receptor alpha

Details

Name
Peroxisome proliferator-activated receptor alpha
Synonyms
  • NR1C1
  • Nuclear receptor subfamily 1 group C member 1
  • PPAR
  • PPAR-alpha
Gene Name
PPARA
Organism
Humans
Amino acid sequence
>lcl|BSEQ0000142|Peroxisome proliferator-activated receptor alpha
MVDTESPLCPLSPLEAGDLESPLSEEFLQEMGNIQEISQSIGEDSSGSFGFTEYQYLGSC
PGSDGSVITDTLSPASSPSSVTYPVVPGSVDESPSGALNIECRICGDKASGYHYGVHACE
GCKGFFRRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGMSHNAIRFGRMPRSE
KAKLKAEILTCEHDIEDSETADLKSLAKRIYEAYLKNFNMNKVKARVILSGKASNNPPFV
IHDMETLCMAEKTLVAKLVANGIQNKEAEVRIFHCCQCTSVETVTELTEFAKAIPGFANL
DLNDQVTLLKYGVYEAIFAMLSSVMNKDGMLVAYGNGFITREFLKSLRKPFCDIMEPKFD
FAMKFNALELDDSDISLFVAAIICCGDRPGLLNVGHIEKMQEGIVHVLRLHLQSNHPDDI
FLFPKLLQKMADLRQLVTEHAQLVQIIKKTESDAALHPLLQEIYRDMY
Number of residues
468
Molecular Weight
52224.595
Theoretical pI
6.2
GO Classification
Functions
DNA binding / drug binding / lipid binding / RNA polymerase II core promoter proximal region sequence-specific DNA binding / RNA polymerase II repressing transcription factor binding / RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding / sequence-specific DNA binding / steroid hormone receptor activity / transcription factor activity, sequence-specific DNA binding / transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding / transcriptional activator activity, RNA polymerase II transcription factor binding / transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding / ubiquitin conjugating enzyme binding / zinc ion binding
Processes
behavioral response to nicotine / cellular lipid metabolic process / circadian regulation of gene expression / circadian rhythm / enamel mineralization / epidermis development / fatty acid metabolic process / fatty acid transport / gene expression / heart development / intracellular receptor signaling pathway / lipid metabolic process / lipoprotein metabolic process / negative regulation of appetite / negative regulation of blood pressure / negative regulation of cholesterol storage / negative regulation of glycolytic process / negative regulation of inflammatory response / negative regulation of leukocyte cell-cell adhesion / negative regulation of macrophage derived foam cell differentiation / negative regulation of neuron death / negative regulation of pri-miRNA transcription from RNA polymerase II promoter / negative regulation of protein binding / negative regulation of receptor biosynthetic process / negative regulation of sequestering of triglyceride / negative regulation of transcription from RNA polymerase II promoter / negative regulation of transcription regulatory region DNA binding / positive regulation of fatty acid beta-oxidation / positive regulation of fatty acid oxidation / positive regulation of gluconeogenesis / positive regulation of transcription from RNA polymerase II promoter / positive regulation of transcription, DNA-templated / regulation of cellular ketone metabolic process by positive regulation of transcription from RNA polymerase II promoter / regulation of circadian rhythm / regulation of glycolytic process by positive regulation of transcription from RNA polymerase II promoter / regulation of lipid transport by positive regulation of transcription from RNA polymerase II promoter / response to hypoxia / response to insulin / small molecule metabolic process / transcription initiation from RNA polymerase II promoter / wound healing
Components
nucleoplasm / nucleus
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0021925|Peroxisome proliferator-activated receptor alpha (PPARA)
ATGGTGGACACGGAAAGCCCACTCTGCCCCCTCTCCCCACTCGAGGCCGGCGATCTAGAG
AGCCCGTTATCTGAAGAGTTCCTGCAAGAAATGGGAAACATCCAAGAGATTTCGCAATCC
ATCGGCGAGGATAGTTCTGGAAGCTTTGGCTTTACGGAATACCAGTATTTAGGAAGCTGT
CCTGGCTCAGATGGCTCGGTCATCACGGACACGCTTTCACCAGCTTCGAGCCCCTCCTCG
GTGACTTATCCTGTGGTCCCCGGCAGCGTGGACGAGTCTCCCAGTGGAGCATTGAACATC
GAATGTAGAATCTGCGGGGACAAGGCCTCAGGCTATCATTACGGAGTCCACGCGTGTGAA
GGCTGCAAGGGCTTCTTTCGGCGAACGATTCGACTCAAGCTGGTGTATGACAAGTGCGAC
CGCAGCTGCAAGATCCAGAAAAAGAACAGAAACAAATGCCAGTATTGTCGATTTCACAAG
TGCCTTTCTGTCGGGATGTCACACAACGCGATTCGTTTTGGACGAATGCCAAGATCTGAG
AAAGCAAAACTGAAAGCAGAAATTCTTACCTGTGAACATGACATAGAAGATTCTGAAACT
GCAGATCTCAAATCTCTGGCCAAGAGAATCTACGAGGCCTACTTGAAGAACTTCAACATG
AACAAGGTCAAAGCCCGGGTCATCCTCTCAGGAAAGGCCAGTAACAATCCACCTTTTGTC
ATACATGATATGGAGACACTGTGTATGGCTGAGAAGACGCTGGTGGCCAAGCTGGTGGCC
AATGGCATCCAGAACAAGGAGGCGGAGGTCCGCATCTTTCACTGCTGCCAGTGCACGTCA
GTGGAGACCGTCACGGAGCTCACGGAATTCGCCAAGGCCATCCCAGGCTTCGCAAACTTG
GACCTGAACGATCAAGTGACATTGCTAAAATACGGAGTTTATGAGGCCATATTCGCCATG
CTGTCTTCTGTGATGAACAAAGACGGGATGCTGGTAGCGTATGGAAATGGGTTTATAACT
CGTGAATTCCTAAAAAGCCTAAGGAAACCGTTCTGTGATATCATGGAACCCAAGTTTGAT
TTTGCCATGAAGTTCAATGCACTGGAACTGGATGACAGTGATATCTCCCTTTTTGTGGCT
GCTATCATTTGCTGTGGAGATCGTCCTGGCCTTCTAAACGTAGGACACATTGAAAAAATG
CAGGAGGGTATTGTACATGTGCTCAGACTCCACCTGCAGAGCAACCACCCGGACGATATC
TTTCTCTTCCCAAAACTTCTTCAAAAAATGGCAGACCTCCGGCAGCTGGTGACGGAGCAT
GCGCAGCTGGTGCAGATCATCAAGAAGACGGAGTCGGATGCTGCGCTGCACCCGCTACTG
CAGGAGATCTACAGGGACATGTACTGA
Chromosome Location
22
Locus
22q12-q13.1|22q13.31
External Identifiers
ResourceLink
UniProtKB IDQ07869
UniProtKB Entry NamePPARA_HUMAN
GenBank Protein ID307341
GenBank Gene IDL02932
GenAtlas IDPPARA
HGNC IDHGNC:9232
General References
  1. Sher T, Yi HF, McBride OW, Gonzalez FJ: cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993 Jun 1;32(21):5598-604. [PubMed:7684926]
  2. Mukherjee R, Jow L, Noonan D, McDonnell DP: Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol. 1994 Nov;51(3-4):157-66. [PubMed:7981125]
  3. Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ: Peroxisome proliferator-activated receptors: structures and function. Ann N Y Acad Sci. 1996 Dec 27;804:252-65. [PubMed:8993548]
  4. Kobayashi T, Kodani Y, Nozawa A, Endo Y, Sawasaki T: DNA-binding profiling of human hormone nuclear receptors via fluorescence correlation spectroscopy in a cell-free system. FEBS Lett. 2008 Aug 6;582(18):2737-44. doi: 10.1016/j.febslet.2008.07.003. Epub 2008 Jul 11. [PubMed:18619963]
  5. Cho MC, Lee S, Choi HS, Yang Y, Tae Hong J, Kim SJ, Yoon DY: Optimization of an enzyme-linked immunosorbent assay to screen ligand of Peroxisome proliferator-activated receptor alpha. Immunopharmacol Immunotoxicol. 2009;31(3):459-67. doi: 10.1080/08923970902785246. [PubMed:19263263]
  6. Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I: A genome annotation-driven approach to cloning the human ORFeome. Genome Biol. 2004;5(10):R84. Epub 2004 Sep 30. [PubMed:15461802]
  7. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039]
  8. Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP, et al.: The DNA sequence of human chromosome 22. Nature. 1999 Dec 2;402(6761):489-95. [PubMed:10591208]
  9. Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA: Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat. J Biol Chem. 1995 Jul 28;270(30):18117-22. [PubMed:7629123]
  10. Li H, Gomes PJ, Chen JD: RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479-84. [PubMed:9238002]
  11. Yan ZH, Karam WG, Staudinger JL, Medvedev A, Ghanayem BI, Jetten AM: Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. J Biol Chem. 1998 May 1;273(18):10948-57. [PubMed:9556573]
  12. Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA: Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. [PubMed:10195690]
  13. Caira F, Antonson P, Pelto-Huikko M, Treuter E, Gustafsson JA: Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J Biol Chem. 2000 Feb 25;275(8):5308-17. [PubMed:10681503]
  14. Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T: Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002 Apr;35(4):937-46. [PubMed:11915042]
  15. Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodriguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D: Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003 Sep 4;425(6953):90-3. [PubMed:12955147]
  16. Park UH, Yoon SK, Park T, Kim EJ, Um SJ: Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor {gamma}. J Biol Chem. 2011 Jan 14;286(2):1354-63. doi: 10.1074/jbc.M110.177816. Epub 2010 Nov 3. [PubMed:21047783]
  17. Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, Cen Y, Jeong SM, Li X, Sauve AA, Haigis MC: SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation. Mol Cell Biol. 2013 Nov;33(22):4552-61. doi: 10.1128/MCB.00087-13. Epub 2013 Sep 16. [PubMed:24043310]
  18. Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT Jr, McKee DD, Moore JT, Willson TM: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13919-24. Epub 2001 Nov 6. [PubMed:11698662]
  19. Cronet P, Petersen JF, Folmer R, Blomberg N, Sjoblom K, Karlsson U, Lindstedt EL, Bamberg K: Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure. 2001 Aug;9(8):699-706. [PubMed:11587644]
  20. Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB: Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature. 2002 Feb 14;415(6873):813-7. [PubMed:11845213]
  21. Oon Han H, Kim SH, Kim KH, Hur GC, Joo Yim H, Chung HK, Ho Woo S, Dong Koo K, Lee CS, Sung Koh J, Kim GT: Design and synthesis of oxime ethers of alpha-acyl-beta-phenylpropanoic acids as PPAR dual agonists. Bioorg Med Chem Lett. 2007 Feb 15;17(4):937-41. Epub 2006 Nov 18. [PubMed:17157019]
  22. Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodeme E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM: Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents. J Med Chem. 2007 Feb 22;50(4):685-95. Epub 2007 Jan 23. [PubMed:17243659]
  23. Oyama T, Toyota K, Waku T, Hirakawa Y, Nagasawa N, Kasuga JI, Hashimoto Y, Miyachi H, Morikawa K: Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures. Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):786-95. doi: 10.1107/S0907444909015935. Epub 2009 Jul 10. [PubMed:19622862]
  24. Benardeau A, Benz J, Binggeli A, Blum D, Boehringer M, Grether U, Hilpert H, Kuhn B, Marki HP, Meyer M, Puntener K, Raab S, Ruf A, Schlatter D, Mohr P: Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes. Bioorg Med Chem Lett. 2009 May 1;19(9):2468-73. doi: 10.1016/j.bmcl.2009.03.036. Epub 2009 Mar 14. [PubMed:19349176]
  25. Artis DR, Lin JJ, Zhang C, Wang W, Mehra U, Perreault M, Erbe D, Krupka HI, England BP, Arnold J, Plotnikov AN, Marimuthu A, Nguyen H, Will S, Signaevsky M, Kral J, Cantwell J, Settachatgull C, Yan DS, Fong D, Oh A, Shi S, Womack P, Powell B, Habets G, West BL, Zhang KY, Milburn MV, Vlasuk GP, Hirth KP, Nolop K, Bollag G, Ibrahim PN, Tobin JF: Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7. doi: 10.1073/pnas.0811325106. Epub 2008 Dec 30. [PubMed:19116277]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB01039FenofibrateapprovedyesagonistDetails
DB01393Bezafibrateapproved, investigationalyesagonistDetails
DB00636Clofibrateapproved, investigationalyesagonistDetails
DB01241GemfibrozilapprovedyesagonistDetails
DB01890N,N-Bis(3-(D-gluconamido)propyl)deoxycholamideexperimentalunknownDetails
DB04971ReglitazarinvestigationalunknownDetails
DB05187ElafibranorinvestigationalunknownDetails
DB06510MuraglitazarinvestigationalunknownDetails
DB06521ErtiprotafibinvestigationalunknownDetails
DB06533RagaglitazarinvestigationalunknownDetails
DB06536TesaglitazarinvestigationalunknownDetails
DB072152-METHYL-2-(4-{[({4-METHYL-2-[4-(TRIFLUOROMETHYL)PHENYL]-1,3-THIAZOL-5-YL}CARBONYL)AMINO]METHYL}PHENOXY)PROPANOIC ACIDexperimentalunknownDetails
DB07724IndeglitazarexperimentalunknownDetails
DB08915AleglitazarinvestigationalyesagonistDetails
DB00328Indometacinapproved, investigationalunknownagonistDetails
DB01708Prasteroneapproved, investigational, nutraceuticalunknownactivatorDetails
DB11133Omega-3 fatty acidsapproved, nutraceuticalunknownactivatorDetails
DB03756Doconexentapproved, investigationalyesligandDetails
DB09422Soybean oilapprovedyesactivatorDetails
DB11605MyrrhapprovedunknownagonistDetails
DB00159Icosapentapproved, nutraceuticalunknownDetails
DB03017Lauric acidapproved, experimentalunknownDetails
DB08231Myristic acidexperimentalunknownDetails
DB03796Palmitic AcidapprovedunknownDetails
DB03193Stearic acidapproved, experimentalunknownDetails
DB04557Arachidonic AcidexperimentalunknownDetails
DB04224Oleic Acidapproved, investigational, vet_approvedunknownDetails
DB00132Alpha-Linolenic Acidapproved, investigational, nutraceuticalunknownDetails
DB09006ClinofibrateexperimentalunknownDetails
DB01132Pioglitazoneapproved, investigationalunknownDetails
DB00412Rosiglitazoneapproved, investigationalunknownDetails
DB00197Troglitazoneinvestigational, withdrawnunknownDetails
DB12961Leukotriene B4investigationalunknownactivatorDetails
DB09064Ciprofibrateapproved, investigationalunknownDetails
DB04519Caprylic acidinvestigationalunknownDetails
DB05416CardarineinvestigationalunknownagonistDetails
DB02746Phthalic AcidexperimentalunknownDetails
DB02709Resveratrolapproved, experimental, investigationalunknownDetails
DB00313Valproic Acidapproved, investigationalunknownDetails
DB00573FenoprofenapprovedunknownactivatorDetails
DB02266Flufenamic AcidapprovedunknownactivatorDetails
DB01050IbuprofenapprovedunknownactivatorDetails
DB13873Fenofibric acidapprovedyesagonistDetails
DB13961Fish oilapproved, nutraceuticalunknownregulatorDetails
DB12007IsoflavoneexperimentalunknownagonistDetails
DB09213Dexibuprofenapproved, investigationalunknownDetails