{{Short description|Group of nuclear receptor proteins}} 450px|thumb|PPAR -alpha and -gamma pathways.
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 gene expression.<ref name="Michalik_2006">{{cite journal | vauthors = 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 | s2cid = 2240461 }}</ref> PPARs play essential roles in regulating cellular differentiation, development, and metabolism (carbohydrate, lipid, protein),<ref>{{Cite journal|last1=Dunning|first1=Kylie R.|last2=Anastasi|first2=Marie R.|last3=Zhang|first3=Voueleng J.|last4=Russell|first4=Darryl L.|last5=Robker|first5=Rebecca L.|date=2014-02-05|title=Regulation of Fatty Acid Oxidation in Mouse Cumulus-Oocyte Complexes during Maturation and Modulation by PPAR Agonists|journal=PLOS ONE|volume=9|issue=2|article-number=e87327|doi=10.1371/journal.pone.0087327|issn=1932-6203|pmc=3914821|pmid=24505284|bibcode=2014PLoSO...987327D|doi-access=free}}</ref> and tumorigenesis<ref name="pmid19609453">{{cite journal | vauthors = Belfiore A, Genua M, Malaguarnera R | title = PPAR-gamma Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer | journal = PPAR Res | volume = 2009 | article-number = 830501 | year = 2009 | pmid = 19609453 | doi = 10.1155/2009/830501 | pmc = 2709717 | doi-access = free }}</ref><ref name="Berger_2002">{{cite journal | vauthors = Berger J, Moller DE | title = The mechanisms of action of PPARs | journal = Annu. Rev. Med. | volume = 53 | pages = 409–35 | year = 2002 | pmid = 11818483 | doi = 10.1146/annurev.med.53.082901.104018 }}</ref><ref name="Feige_2006">{{cite journal | vauthors = 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 }}</ref>
== Nomenclature and tissue distribution == {{infobox protein | Name = Peroxisome proliferator-activated receptor alpha | caption = | image = | 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 = -q13.1 }} {{infobox protein | Name = Peroxisome proliferator-activated receptor gamma | caption = | image = PPARg.png | width = | HGNCid = 9236 | Symbol = PPARG | AltSymbols = | EntrezGene = 5468 | OMIM = 601487 | RefSeq = NM_005037 | UniProt = P37231 | PDB = | ECnumber = | Chromosome = 3 | Arm = p | Band = 25 | LocusSupplementaryData = }} {{infobox protein | Name = Peroxisome proliferator-activated receptor delta | caption = | image = | 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):<ref name="Berger_2002" /> * '''α''' (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others<ref name="pmid22247890">{{cite journal |vauthors=Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S |title=The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases |journal=J Adv Pharm Technol Res |volume=2 |issue=4 |pages=236–40 |date=October 2011 |pmid=22247890 |pmc=3255347 |doi=10.4103/2231-4040.90879 |doi-access=free }}</ref> * '''β/δ''' (beta/delta) - expressed in many tissues, especially in brain, adipose tissue, and skin * '''γ''' (gamma) - although transcribed by the same gene, this PPAR, by way of alternative splicing, is expressed in three forms: ** γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen ** γ2 - expressed mainly in adipose tissue; it is 30 amino acids longer than γ1 ** γ3 - expressed in macrophages, large intestine, white adipose tissue
== History == These agents, pharmacologically related to the fibrates, were discovered in the early 1980s.
PPARs were originally identified in ''Xenopus'' frogs as receptors that induce the proliferation of peroxisomes in cells in 1992.<ref name="pmid1312391">{{cite journal | vauthors = 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 | s2cid = 3148132 }}</ref> The first PPAR (PPARα) was discovered in 1990 during the search for a molecular target of a group of agents then referred to as ''peroxisome proliferators'', as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.<ref name="pmid2129546">{{cite journal | vauthors = 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 | bibcode = 1990Natur.347..645I | s2cid = 4306126 }}</ref>
When it turned out that PPARs played a versatile role in biology, the agents were in turn termed ''PPAR ligands''. The best-known PPAR ligands are the thiazolidinediones.
After PPARδ (delta) was identified in humans in 1992,<ref name="pmid1333051">{{cite journal | vauthors = 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 | doi = 10.1210/mend.6.10.1333051 | pmid = 1333051 | s2cid = 23506853 | doi-access = free }}</ref> it turned out to be closely related to PPARβ (beta), previously described during the same year in an amphibian, ''Xenopus''. The term "PPARδ" is generally used in the US, while "PPARβ" has remained in Europe, where this receptor was initially discovered.
PPARs were named because they induce peroxisome proliferation in rodents, but this induction has not been verified in humans.<ref name="pmid29197930">{{cite journal | vauthors=Corton JC, Peters JM, Klaunig JE | title=The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions | journal=Journal of Molecular Endocrinology | volume=92 | issue=1 | pages=83–119 | year=2018 | doi = 10.1007/s00204-017-2094-7 | pmc=6092738 | pmid=29197930 | bibcode=2018ArTox..92...83C }}</ref><ref> {{cite book |chapter=Peroxisome Proliferator-Activated Receptors |vauthors=Sugden MC, Caton PW, Holness MJ, Miller JJ |title= Reference Module in Life Sciences|doi=10.1016/B978-0-12-819460-7.00200-0|chapter-url=https://www.sciencedirect.com/science/article/pii/B9780128194607002000|date=2021|volume=17|issue= 6|pages= 574–583 |publisher= Elsevier|isbn= 978-0-12-809633-8|s2cid= 241510571}}</ref>
== Physiological function == All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequence is AGGTCANAGGTCA, with N being any nucleotide. In general, this sequence occurs in the promoter 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.<ref name="pmid17306620">{{cite journal | vauthors = 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 }}</ref>
Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3. PPARγ is activated by PGJ<sub>2</sub> (a prostaglandin) and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE.<ref>Biochim. Biophys. Acta 1736:228–236, 2005</ref> In contrast, PPARα is activated by leukotriene B<sub>4</sub>. Certain members of the 15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, including 15(S)-HETE, 15(R)-HETE, and 15-HpETE activate to varying degrees PPAR alpha, beta/delta, and gamma. In addition, PPARγ was reported to be involved in cancer pathogenesis and growth.<ref >{{cite journal | vauthors = Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ | title = Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance | journal = Journal of Physiology and Biochemistry | volume = 77 | issue = 2 | pages = 249–260 | date = May 2021 | pmid = 33730333 | doi = 10.1007/s13105-021-00791-3 | s2cid = 232300877 | issn = }}</ref><ref>Mol. Pharmacol. 77-171-184, 2010</ref> PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.<ref name="pmid19208833">{{cite journal | vauthors = Marlow LA, Reynolds LA, Cleland AS, Cooper SJ, Gumz ML, Kurakata S, Fujiwara K, Zhang Y, Sebo T, Grant C, McIver B, Wadsworth JT, Radisky DC, Smallridge RC, Copland JA | title = Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth | journal = Cancer Res. | volume = 69 | issue = 4 | pages = 1536–44 |date=February 2009 | pmid = 19208833 | doi = 10.1158/0008-5472.CAN-08-3718 | pmc = 2644344 }}</ref> See<ref>Curr. Mol. Med. 7:532–540, 2007</ref> for a review and critique of the roles of PPAR gamma in cancer.
== Genetics == The three main forms of PPAR are transcribed from different genes: * PPARα - chromosome 22q12-13.1 (OMIM [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=170998 170998]{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}) * PPARβ/δ - chromosome 6p21.2-21.1 (OMIM [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=600409 600409]{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}) * PPARγ - chromosome 3p25 (OMIM [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=601487 601487]{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}).
Hereditary disorders of all 3 of these PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans.<ref name="pmid15464424">{{cite journal | vauthors = 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 }}</ref> Of PPARγ, a gain-of-function mutation has been described and studied: Pro12Ala, which decreases the risk of insulin resistance. It is quite prevalent, with an allele frequency of 0.03 - 0.12 in some populations.<ref name="pmid15367918">{{cite journal | vauthors = 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 = European Journal of Human Genetics | volume = 12 | issue = 12 | pages = 1050–4 | year = 2004 | pmid = 15367918 | doi = 10.1038/sj.ejhg.5201283 | doi-access = free }}</ref> In contrast, pro115gln is associated with obesity. Certain other polymorphisms in PPAR show a 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 region
The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated.
The LBD has an extensive secondary structure consisting of 13 alpha helices and a beta sheet.<ref name="pmid17317294">{{cite journal | vauthors = 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 }}</ref> Both natural and synthetic ligands can bind to the LBD, either activating or repressing the receptor's activity.
== Pharmacology and PPAR modulators == {{main article|PPAR modulator}} PPARα and PPARγ are the molecular targets of a number of marketed drugs.
For instance the hypolipidemic fibrates activate PPARα.{{cn|date=March 2023}}
The anti diabetic thiazolidinediones activate PPARγ.{{cn|date=March 2023}}
The synthetic chemical perfluorooctanoic acid activates PPARα while perfluorononanoic acid activates both PPARα and PPARγ. {{cn|date=March 2023}}
Berberine inactivates PPARγ.<ref>{{cite journal | vauthors = Huang C, Zhang Y, Gong Z, Sheng X, Li Z, Zhang W, Qin Y | title = Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway | journal = Biochemical and Biophysical Research Communications | volume = 348 | issue = 2 | pages = 571–578 | year = 2006 | doi = 10.1016/j.bbrc.2006.07.095| pmid = 16890192 }}</ref>
Other natural compounds from different chemical classes activate or inactivate PPARγ.<ref name="pmid23811337">{{cite journal | vauthors = Atanasov AG, Wang JN, Gu SP, Bu J, Kramer MP, Baumgartner L, Fakhrudin N, Ladurner A, Malainer C, Vuorinen A, Noha SM, Schwaiger S, Rollinger JM, Schuster D, Stuppner H, Dirsch VM, Heiss EH | title = Honokiol: a non-adipogenic PPARγ agonist from nature | journal = Biochim. Biophys. Acta | volume = 1830 | issue = 10 | pages = 4813–9 | year = 2013 | pmid = 23811337 | pmc = 3790966 | doi = 10.1016/j.bbagen.2013.06.021 }}</ref><ref name="pmid23630612">{{cite journal | vauthors = Atanasov AG, Blunder M, Fakhrudin N, Liu X, Noha SM, Malainer C, Kramer MP, Cocic A, Kunert O, Schinkovitz A, Heiss EH, Schuster D, Dirsch VM, Bauer R | title = Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma | journal = PLOS ONE | volume = 8 | issue = 4 | article-number = e61755 | year = 2013 | pmid = 23630612 | pmc = 3632601 | doi = 10.1371/journal.pone.0061755 | bibcode = 2013PLoSO...861755A | doi-access = free }}</ref><ref>{{Cite journal |last1=Ammazzalorso |first1=Alessandra |last2=Amoroso |first2=Rosa |date=2019-02-28 |title=Inhibition of PPARγ by Natural Compounds as a Promising Strategy in Obesity and Diabetes |url=https://openmedicinalchemistryjournal.com/VOLUME/13/PAGE/7/FULLTEXT/ |journal=The Open Medicinal Chemistry Journal |language=en |volume=13 |issue=1 |pages=7–15 |doi=10.2174/1874104501913010007|doi-access=free }}</ref>
== See also == * Metabolic syndrome *Endocannabinoid system
==References== {{Reflist|2}}
== External links == * [http://ppar.cas.psu.edu] (PPAR Resource Page, Penn State University). * [http://www.joshuapgray.com/Framed%20Nuclear%20Receptor%20outline/Main%20outline%20page.htm PPAR reference outline] {{Webarchive|url=https://web.archive.org/web/20200214171006/http://www.joshuapgray.com/Framed%20Nuclear%20Receptor%20outline/Main%20outline%20page.htm |date=2020-02-14 }} (Rutgers University). * {{MeshName|Peroxisome+Proliferator-Activated+Receptors}} * {{Proteopedia|Peroxisome_Proliferator-Activated_Receptors}} - the Peroxisome Proliferator-Activated Receptor Structure in Interactive 3D
{{Transcription factors|g2}} {{PPAR modulators}}
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