- Peroxisome proliferator-activated receptor
In the field of
molecular biology , the peroxisome proliferator-activated receptors (PPARs) are a group ofnuclear receptor protein s that function astranscription factor s regulating the expression ofgene s.cite journal | author = Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W | title = International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors | journal = Pharmacol. Rev. | volume = 58 | issue = 4 | pages = 726–41 | year = 2006 | pmid = 17132851 | doi = 10.1124/pr.58.4.5 ] PPARs play essential roles in the regulation of cellular differentiation, development, andmetabolism (carbohydrate, lipid, and protein) of higher organisms.cite journal | author = Berger J, Moller DE | title = The mechanisms of action of PPARs | journal = Annu. Rev. Med. | volume = 53 | issue = | pages = 409–35 | year = 2002 | pmid = 11818483 | doi = 10.1146/annurev.med.53.082901.104018 ] cite journal | author = Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W | title = From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions | journal = Prog. Lipid Res. | volume = 45 | issue = 2 | pages = 120–59 | year = 2006 | pmid = 16476485 | doi = 10.1016/j.plipres.2005.12.002 ]Nomenclature and tissue distribution
protein
Name =Peroxisome proliferator-activated receptor alpha
caption =
width =
HGNCid = 9232
Symbol = PPARA
AltSymbols = PPAR
EntrezGene = 5465
OMIM = 170998
RefSeq = NM_001001928
UniProt = Q07869
PDB =
ECnumber =
Chromosome = 22
Arm = q
Band = 12
LocusSupplementaryData = -q13.1protein
Name =Peroxisome proliferator-activated receptor gamma
caption =
width =
HGNCid = 9236
Symbol = PPARG
AltSymbols =
EntrezGene = 5468
OMIM = 601487
RefSeq = NM_005037
UniProt = P37231
PDB =
ECnumber =
Chromosome = 3
Arm = p
Band = 25
LocusSupplementaryData = protein
Name =Peroxisome proliferator-activated receptor delta
caption =
width =
HGNCid = 9235
Symbol = PPARD
AltSymbols =
EntrezGene = 5467
OMIM = 600409
RefSeq = NM_006238
UniProt = Q03181
PDB =
ECnumber =
Chromosome = 6
Arm = p
Band = 21.2
LocusSupplementaryData = Three types of PPARs have been identified: alpha, gamma, and delta (beta):
* α (alpha) - expressed inliver ,kidney ,heart ,muscle ,adipose tissue , and others
* β/δ (beta/delta) - expressed in many tissues but markedly inbrain ,adipose tissue , andskin
* γ (gamma) - although transcribed by the same gene, this PPAR throughalternative splicing is expressed in three forms:
** γ1 - expressed in virtually all tissues, includingheart ,muscle , colon,kidney ,pancreas , andspleen
** γ2 - expressed mainly inadipose tissue (30amino acid s longer)
** γ3 - expressed inmacrophage s, large intestine, whiteadipose tissue .History
PPARs were originally identified in
Xenopus frogs as receptors that induce the proliferation ofperoxisome s in cells.cite journal | author = Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W | title = Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors | journal = Cell | volume = 68 | issue = 5 | pages = 879–87 | year = 1992 | pmid = 1312391 | doi = 10.1016/0092-8674(92)90031-7 ] The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as "peroxisome proliferators", as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.cite journal | author = Issemann I, Green S | title = Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators | journal = Nature | volume = 347 | issue = 6294 | pages = 645–50 | year = 1990 | pmid = 2129546 | doi = 10.1038/347645a0 ] These agents, pharmacologically related to thefibrate s were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed "PPAR ligands". The best-known PPAR ligands are thethiazolidinedione s; see below for more details.After PPARδ (delta) was identified in humans in 1992,cite journal | author = Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA | title = Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids | journal = Mol. Endocrinol. | volume = 6 | issue = 10 | pages = 1634–41 | year = 1992 | pmid = 1333051 | doi = 10.1210/me.6.10.1634 ] it turned out to be closely-related to the PPARβ (beta) previously described during the same year in other animals (
Xenopus ). The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.Physiological function
All PPARs heterodimerize with the
retinoid X receptor (RXR) and bind to specific regions on theDNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferatorhormone response element s). The DNAconsensus sequence is AGGTCAXAGGTCA, with X being a randomnucleotide . In general, this sequence occurs in the promotor region of agene , and, when the "PPAR" binds its ligand, transcription of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone).The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.cite journal | author = Yu S, Reddy JK | title = Transcription coactivators for peroxisome proliferator-activated receptors | journal = Biochim. Biophys. Acta | volume = 1771 | issue = 8 | pages = 936–51 | year = 2007 | pmid = 17306620 | doi = 10.1016/j.bbalip.2007.01.008 ]
Endogenous ligands for the PPARs include
free fatty acid s andeicosanoid s.PPARγ is activated by PGJ2 (a prostaglandin). In contrast, PPARα is activated byleukotriene B4.Genetics
The three main forms are transcribed from different
gene s:
* PPARα -chromosome 22q12-13.1 (OMIM [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=170998 170998] )
* PPARβ/δ - chromosome 6p21.2-21.1 (OMIM [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=600409 600409] )
*PPARγ - chromosome 3p25 (OMIM [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=601487 601487] ).Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant
lipodystrophy ,insulin resistance , and/oracanthosis nigricans .cite journal | author = Meirhaeghe A, Amouyel P | title = Impact of genetic variation of PPARgamma in humans | journal = Mol. Genet. Metab. | volume = 83 | issue = 1-2 | pages = 93–102 | year = 2004 | pmid = 15464424 | doi = 10.1016/j.ymgme.2004.08.014 ] OfPPARγ , a gain-of-functionmutation has been described and studied (Pro12Ala) which decreased the risk ofinsulin resistance ; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations).cite journal | author = Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Di Mario U | title = The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity | journal = Eur. J. Hum. Genet. | volume = 12 | issue = 12 | pages = 1050–4 | year = 2004 | pmid = 15367918 | doi = 10.1038/sj.ejhg.5201283 ] In contrast, pro115gln is associated withobesity . Some other polymorphisms have high incidence in populations with elevated body mass indexes.Structure
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:
* (A/B) N-terminal region
* (C) "DBD" (DNA-binding domain )
* (D) flexible hinge region
* (E) "LBD" (ligand binding domain)
* (F) C-terminal regionThe DBD contains two
zinc finger motifs, which bind to specific sequences of DNA known ashormone response element s when the receptor is activated. The LBD has an extensivesecondary structure consisting of 13 alpha helices and abeta sheet .cite journal | author = Zoete V, Grosdidier A, Michielin O | title = Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators | journal = Biochim. Biophys. Acta | volume = 1771 | issue = 8 | pages = 915–25 | year = 2007 | pmid = 17317294 | doi = 10.1016/j.bbalip.2007.01.007 ] Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.Pharmacology and PPAR modulators
PPARα and PPARγ are the molecular targets of a number of marketed
drug s.See also
*
Thiazolidinedione
*Anti-diabetic drug
*Diabetes mellitus
*Insulin resistance
*Metabolic syndrome References
External links
* [http://www.cas.psu.edu/docs/CASDEPT/VET/jackvh/ppar/pparrfront.htm PPAR resource] (Penn State University).
* [http://www.joshuapgray.com/Framed%20Nuclear%20Receptor%20outline/Main%20outline%20page.htm PPAR reference outline] (Rutgers University).
*
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