- Peroxisome proliferator-activated receptor
In the field of
molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes.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, and metabolism(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
Peroxisome proliferator-activated receptor alpha
HGNCid = 9232
Symbol = PPARA
AltSymbols = PPAR
EntrezGene = 5465
OMIM = 170998
RefSeq = NM_001001928
UniProt = Q07869
Chromosome = 22
Arm = q
Band = 12
LocusSupplementaryData = -q13.1protein
Peroxisome proliferator-activated receptor gamma
HGNCid = 9236
Symbol = PPARG
EntrezGene = 5468
OMIM = 601487
RefSeq = NM_005037
UniProt = P37231
Chromosome = 3
Arm = p
Band = 25
LocusSupplementaryData = protein
Peroxisome proliferator-activated receptor delta
HGNCid = 9235
Symbol = PPARD
EntrezGene = 5467
OMIM = 600409
RefSeq = NM_006238
UniProt = Q03181
Chromosome = 6
Arm = p
Band = 21.2
LocusSupplementaryData = Three types of PPARs have been identified: alpha, gamma, and delta (beta):
* α (alpha) - expressed in
liver, kidney, heart, muscle, adipose tissue, and others
* β/δ (beta/delta) - expressed in many tissues but markedly in
brain, adipose tissue, and skin
* γ (gamma) - although transcribed by the same gene, this PPAR through
alternative splicingis expressed in three forms:
** γ1 - expressed in virtually all tissues, including
heart, muscle, colon, kidney, pancreas, and spleen
** γ2 - expressed mainly in
adipose tissue(30 amino acids longer)
** γ3 - expressed in
macrophages, large intestine, white adipose tissue.
PPARs were originally identified in
Xenopusfrogs as receptors that induce the proliferation of peroxisomes 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 the fibrates 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 the thiazolidinediones; 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.
All PPARs heterodimerize with the
retinoid X receptor(RXR) and bind to specific regions on the DNAof target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequenceis AGGTCAXAGGTCA, with X being a random nucleotide. In general, this sequence occurs in the promotor region of a gene, 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 acids and eicosanoids. PPARγis activated by PGJ2 (a prostaglandin). In contrast, PPARα is activated by leukotrieneB4.
The three main forms are transcribed from different
* PPARα -
chromosome22q12-13.1 (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/or acanthosis 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 ] Of PPARγ, a gain-of-function mutationhas been described and studied (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent ( allelefrequency 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 with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:
* (A/B) N-terminal region
* (C) "DBD" (
* (D) flexible hinge region
* (E) "LBD" (ligand binding domain)
* (F) C-terminal region
The DBD contains two
zinc fingermotifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. The LBD has an extensive secondary structureconsisting of 13 alpha helices and a beta 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
* [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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