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[[File:PPAR-diagram.png|450px|thumb|PPAR -alpha and -gamma pathways.]]
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In the field of [[molecular biology]], the '''peroxisome proliferator-activated receptors''' ('''PPARs''') are a group of [[nuclear receptor]] [[protein]]s that function as [[transcription factor]]s regulating the expression of [[gene]]s.<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 }}</ref>  PPARs play essential roles in the regulation of [[cell differentiation|cellular differentiation]], [[developmental biology|development]], and [[metabolism]] ([[carbohydrate metabolism|carbohydrate]], [[lipid metabolism|lipid]], [[protein metabolism|protein]]),<ref>{{Cite journal|last=Dunning|first=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|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087327|journal=PLOS ONE|volume=9|issue=2|pages=e87327|doi=10.1371/journal.pone.0087327|issn=1932-6203|pmc=3914821|pmid=24505284}}</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 | issue = | pages = 830501 | year = 2009 | pmid = 19609453 | doi = 10.1155/2009/830501 | url = | issn = | pmc = 2709717 }}</ref> of higher organisms.<ref name="Berger_2002">{{cite journal | vauthors = 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 }}</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>


==Overview==
== Nomenclature and tissue distribution ==
 
{{infobox protein
In [[cell biology]], '''peroxisome proliferator-activated receptors''' ('''PPARs''') are a group of [[nuclear receptor]] isoforms that exist across [[biology]]. They are intimately connected to cellular [[metabolism]] ([[carbohydrate_metabolism|carbohydrate]], [[lipid_metabolism|lipid]] and [[protein_metabolism|protein]]) and [[cell differentiation]]. They are [[transcription factor]]s.
| Name = [[Peroxisome proliferator-activated receptor alpha]]
 
| caption =  
== Nomenclature ==
| image =  
{{protein
| Name = peroxisome proliferative activated receptor, alpha
| caption = PPAR -alpha and -gamma pathways
| image = PPAR-diagram.png
| width =  
| width =  
| HGNCid = 9232
| HGNCid = 9232
Line 27: Line 23:
| LocusSupplementaryData = -q13.1
| LocusSupplementaryData = -q13.1
}}
}}
{{protein
{{infobox protein
| Name = peroxisome proliferative activated receptor, gamma
| Name = [[Peroxisome proliferator-activated receptor gamma]]
| caption = PPAR gamma
| caption =  
| image = PPARg.png
| image = PPARg.png
| width =  
| width =  
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| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
{{protein
{{infobox protein
| Name = peroxisome proliferative activated receptor, delta
| Name = [[Peroxisome proliferator-activated receptor delta]]
| caption =  
| caption =  
| image =  
| image =  
Line 65: Line 61:
| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
Three types of PPARs have been identified: alpha, [[PPARG|gamma]], and delta (beta):<ref name="Berger_2002" />
* [[Peroxisome proliferator-activated receptor alpha|'''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 |url=http://www.japtr.org/article.asp?issn=2231-4040;year=2011;volume=2;issue=4;spage=236;epage=240;aulast=Tyagi}}</ref>
* [[Peroxisome proliferator-activated receptor delta|'''β/δ''' (beta/delta)]] - expressed in many tissues but markedly in [[brain]], [[adipose tissue]], and [[skin]]
* [[Peroxisome proliferator-activated receptor gamma|'''γ''' (gamma)]] - although transcribed by the same gene, this PPAR through [[alternative splicing]] is expressed in three forms:
** γ1 - expressed in virtually all tissues, including [[heart]], [[muscle]], [[colon (anatomy)|colon]], [[kidney]], [[pancreas]], and [[spleen]]
** γ2 - expressed mainly in [[adipose tissue]] (30 [[amino acid]]s longer than γ1)
** γ3 - expressed in [[macrophage]]s, [[colon (anatomy)|large intestine]], [[white adipose tissue]].


Three types of PPARs have been identified: alpha, gamma and delta (beta).
=== History ===
* '''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 exists in three forms:
** γ1 - expressed in virtually all tissues, including [[heart]], [[muscle]], [[colon (anatomy)|colon]], [[kidney]], [[pancreas]] and [[spleen]].
** γ2 - expressed mainly in [[adipose tissue]] (30 [[amino acid]]s longer)
** γ3 - expressed in [[macrophage]]s, [[colon (anatomy)|large intestine]], white [[adipose tissue]].


===History===
PPARs were originally identified in ''[[Xenopus]]'' frogs as receptors that induce the proliferation of [[peroxisome]]s in cells.<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 }}</ref>
PPARs were originally identified in [[Xenopus]] frogs as receptors that induce the proliferation of [[peroxisome]]s in cells.
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 resistance|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 }}</ref> These agents, [[pharmacology|pharmacologically]] related to the [[fibrate]]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 the [[thiazolidinedione]]s; see below for more details.
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 [[peroxisome]]s in rodent liver tissue, apart from improving [[insulin resistance|insulin sensitivity]]. These agents, [[pharmacology|pharmacologically]] related to the [[fibrate]]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 the [[thiazolidinedione]]s; see below for more details.


After PPARδ (delta) was identified in humans in 1992, 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.
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 | pmid = 1333051 | doi = 10.1210/me.6.10.1634 }}</ref> 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 ==
== Physiological function ==
All PPARs dimerize 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 response elements). The DNA [[consensus sequence]] is AGGTCA'''X'''AGGTCA with X being a random [[nucleotide]]. Generally, this sequence occurs in the promotor region of a [[gene]], and when the ''PPAR'' binds its ligand, [[Transcription (genetics)|transcription]] of targets genes are increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors: the [[vitamin D]] receptor and the [[thyroid hormone]] receptor.
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 element]]s). 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 (genetics)|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., [[calcitriol receptor|vitamin D]] and [[thyroid hormone receptor|thyroid hormone]]).


The function of PPARs is modified by the exact shape of their ligand-binding domain (see below) and by a number of ''co-activators'' and ''co-repressors'', the presence of which can stimulate or inhibit receptor function.  
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 (genetics)|coactivator]] and [[corepressor (genetics)|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>


The ligands for the PPARs are [[free fatty acid]]s and [[eicosanoid]]s. PPARγ is activated by [[prostaglandin|PGJ<sub>2</sub>]] (a prostaglandin). In contrast, PPARα is activated by [[leukotriene]] B<sub>4</sub>.
Endogenous ligands for the PPARs include [[free fatty acid]]s and [[eicosanoid]]s. [[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|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.<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 | url = | issn = | 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 ==
== Genetics ==
The three main forms are transcribed from different [[gene]]s:
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]).
* PPARα - [[chromosome 22]]q12-13.1 (OMIM [https://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]).
* PPARβ/δ - [[chromosome 6]]p21.2-21.1 (OMIM [https://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]).
* [[PPARγ]] - [[chromosome 3]]p25 (OMIM [https://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]]. Of PPARγ, a gain-of-function [[mutation]] has been described and studied ([[Proline|Pro]]12[[Alanine|Ala]]) which decreased the risk of [[insulin resistance]]; it is quite prevalent ([[allele]] frequency 0.03 - 0.12 in some populations). In contrast, [[Proline|pro]]115[[glutamine|gln]] is associated with [[obesity]]. Some other polymorphisms have high incidence in populations with elevated body mass indexes.
Hereditary disorders of all 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 ([[Proline|Pro]]12[[Alanine|Ala]]) which decreased the risk of [[insulin resistance]]; it is quite prevalent ([[allele]] frequency 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 }}</ref> In contrast, [[Proline|pro]]115[[glutamine|gln]] is associated with [[obesity]]. Some other polymorphisms have high incidence in populations with elevated body mass indexes.


== Structure ==
== Structure ==
Like other nuclear receptors, PPARs are modular in structure and contain the following [[protein domains|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


All PPARs have a basic structure of functional domains. The most important ones are the ''DBD'' (DNA binding domain) and the ''LBD'' (ligand binding domain). The DBD contains two [[zinc finger]] patterns which bind to the regulator region of DNA when the receptor is activated. The LBD has an extensive [[secondary structure]] of several [[alpha helix|alpha helices]] (13) and a [[beta sheet]]. Natural and synthetic ligands bind to the LBD, activating the receptor.
The DBD contains two [[zinc finger]] motifs, which bind to specific sequences of DNA known as [[hormone response element]]s when the receptor is activated. The LBD has an extensive [[secondary structure]] consisting of 13 [[alpha helix|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>  Natural and synthetic ligands bind to the LBD, either [[agonist|activating]] or [[receptor antagonist|repressing]] the receptor.
 
== Pharmacology and PPAR modulators==
PPARα and PPARγ are the targets of a number of known [[medication]]s and are under continuing research for other forms of [[pharmacology|pharmacological]] modulation. [[Muraglitazar]] and [[tesaglitazar]], both experimental compounds, binds to both PPAR-alpha and PPAR-gamma.


===PPAR-alpha modulators===
== Pharmacology and PPAR modulators ==
PPAR-alpha is the main target of [[fibrate]] [[medication|drugs]], a class of amphipathic carboxylic acids ([[clofibrate]], [[gemfibrozil]], [[ciprofibrate]], [[bezafibrate]] and [[fenofibrate]]). They are used in [[cholesterol]] disorders (generally as an adjunctive to [[statin]]s) and disorders that feature high [[triglyceride]]s.
{{main article|PPAR modulator}}
 
PPARα and PPARγ are the molecular targets of a number of marketed [[drug]]s. For instance the [[Hypolipidemic agent|hypolipidemic]] [[fibrate]]s activate PPARα, and the [[anti-diabetic drugs|anti diabetic]] [[thiazolidinediones]] activate PPARγ. The synthetic chemical [[perfluorooctanoic acid]] activates PPARα while the synthetic [[perfluorononanoic acid]] activates both PPARα and PPARγ. [[Berberine]] activates PPARγ, as well as other natural compounds from different chemical classes.<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 | pages = e61755 | year = 2013 | pmid = 23630612 | pmc = 3632601 | doi = 10.1371/journal.pone.0061755 }}</ref>
===PPAR-gamma modulators===
PPAR-gamma is the main target of the drug class of [[thiazolidinedione]]s (TZDs), used in [[diabetes mellitus]] and other diseases that feature [[insulin resistance]]. It is also mildly activated by certain [[NSAID]]s (such as [[ibuprofen]]) and [[indole]]s. Known inhibitors include the experimental agent GW-9662.


== See also ==
== See also ==
Line 115: Line 112:
* [[Metabolic syndrome]]
* [[Metabolic syndrome]]


== Sources ==
==References==
* {{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 | issn = }}
{{Reflist|2}}
* {{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 | issn = }}
* {{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 | issn = }}


== External links ==
== External links ==
* [http://www.cas.psu.edu/docs/CASDEPT/VET/jackvh/ppar/pparrfront.htm PPAR resource] (Penn State University).
* [http://ppar.cas.psu.edu] (PPAR Resource Page, Penn State University).
* [http://nrresource.org] (Nuclear Receptor Resource).
* [http://www.joshuapgray.com/Framed%20Nuclear%20Receptor%20outline/Main%20outline%20page.htm PPAR reference outline] (Rutgers University).
* [http://www.joshuapgray.com/Framed%20Nuclear%20Receptor%20outline/Main%20outline%20page.htm PPAR reference outline] (Rutgers University).
* {{MeshName|Peroxisome+Proliferator-Activated+Receptors}}
* {{MeshName|Peroxisome+Proliferator-Activated+Receptors}}
* {{Proteopedia|Peroxisome_Proliferator-Activated_Receptors}} - the Peroxisome Proliferator-Activated Receptor Structure in Interactive 3D
{{Transcription factors|g2}}
{{PPAR modulators}}


{{Transcription factors}}
[[Category:Intracellular receptors]]
[[Category:Intracellular receptors]]
 
[[Category:Transcription factors]]
[[fr:Peroxisome proliferator-activated receptor]]
[[ja:PPAR]]
 
{{WH}}
{{WS}}

Latest revision as of 12:19, 9 January 2019

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 the expression of genes.[1] PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein),[2] and tumorigenesis[3] of higher organisms.[4][5]

Nomenclature and tissue distribution

Peroxisome proliferator-activated receptor alpha
Identifiers
SymbolPPARA
Alt. symbolsPPAR
Entrez5465
HUGO9232
OMIM170998
RefSeqNM_001001928
UniProtQ07869
Other data
LocusChr. 22 q12-q13.1
Peroxisome proliferator-activated receptor gamma
Identifiers
SymbolPPARG
Entrez5468
HUGO9236
OMIM601487
RefSeqNM_005037
UniProtP37231
Other data
LocusChr. 3 p25
Peroxisome proliferator-activated receptor delta
Identifiers
SymbolPPARD
Entrez5467
HUGO9235
OMIM600409
RefSeqNM_006238
UniProtQ03181
Other data
LocusChr. 6 p21.2

Three types of PPARs have been identified: alpha, gamma, and delta (beta):[4]

History

PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells.[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.[8] 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,[9] 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 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.[10]

Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPARγ is activated by PGJ2 (a prostaglandin) and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE.[11] In contrast, PPARα is activated by leukotriene B4. 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.[12] PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.[13] See[14] for a review and critique of the roles of PPAR gamma in cancer.

Genetics

The three main forms are transcribed from different genes:

Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans.[15] Of PPARγ, a gain-of-function mutation has been described and studied (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations).[16] In contrast, pro115gln is associated with obesity. 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 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.[17] Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.

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, and the anti diabetic thiazolidinediones activate PPARγ. The synthetic chemical perfluorooctanoic acid activates PPARα while the synthetic perfluorononanoic acid activates both PPARα and PPARγ. Berberine activates PPARγ, as well as other natural compounds from different chemical classes.[18][19]

See also

References

  1. ↑ 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 (2006). "International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors". Pharmacol. Rev. 58 (4): 726–41. doi:10.1124/pr.58.4.5. PMID 17132851.
  2. ↑ Dunning, Kylie R.; Anastasi, Marie R.; Zhang, Voueleng J.; Russell, Darryl L.; Robker, Rebecca L. (2014-02-05). "Regulation of Fatty Acid Oxidation in Mouse Cumulus-Oocyte Complexes during Maturation and Modulation by PPAR Agonists". PLOS ONE. 9 (2): e87327. doi:10.1371/journal.pone.0087327. ISSN 1932-6203. PMC 3914821. PMID 24505284.
  3. ↑ Belfiore A, Genua M, Malaguarnera R (2009). "PPAR-gamma Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer". PPAR Res. 2009: 830501. doi:10.1155/2009/830501. PMC 2709717. PMID 19609453.
  4. ↑ 4.0 4.1 Berger J, Moller DE (2002). "The mechanisms of action of PPARs". Annu. Rev. Med. 53: 409–35. doi:10.1146/annurev.med.53.082901.104018. PMID 11818483.
  5. ↑ Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006). "From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions". Prog. Lipid Res. 45 (2): 120–59. doi:10.1016/j.plipres.2005.12.002. PMID 16476485.
  6. ↑ Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S (October 2011). "The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases". J Adv Pharm Technol Res. 2 (4): 236–40. doi:10.4103/2231-4040.90879. PMC 3255347. PMID 22247890.
  7. ↑ Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992). "Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors". Cell. 68 (5): 879–87. doi:10.1016/0092-8674(92)90031-7. PMID 1312391.
  8. ↑ Issemann I, Green S (1990). "Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators". Nature. 347 (6294): 645–50. doi:10.1038/347645a0. PMID 2129546.
  9. ↑ Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA (1992). "Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids". Mol. Endocrinol. 6 (10): 1634–41. doi:10.1210/me.6.10.1634. PMID 1333051.
  10. ↑ Yu S, Reddy JK (2007). "Transcription coactivators for peroxisome proliferator-activated receptors". Biochim. Biophys. Acta. 1771 (8): 936–51. doi:10.1016/j.bbalip.2007.01.008. PMID 17306620.
  11. ↑ Biochim. Biophys. Acta 1736:228-236, 2005
  12. ↑ Mol. Pharmacol. 77-171-184, 2010
  13. ↑ 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 (February 2009). "Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth". Cancer Res. 69 (4): 1536–44. doi:10.1158/0008-5472.CAN-08-3718. PMC 2644344. PMID 19208833.
  14. ↑ Curr. Mol. Med. 7:532-540, 2007
  15. ↑ Meirhaeghe A, Amouyel P (2004). "Impact of genetic variation of PPARgamma in humans". Mol. Genet. Metab. 83 (1–2): 93–102. doi:10.1016/j.ymgme.2004.08.014. PMID 15464424.
  16. ↑ 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 (2004). "The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity". European Journal of Human Genetics. 12 (12): 1050–4. doi:10.1038/sj.ejhg.5201283. PMID 15367918.
  17. ↑ Zoete V, Grosdidier A, Michielin O (2007). "Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators". Biochim. Biophys. Acta. 1771 (8): 915–25. doi:10.1016/j.bbalip.2007.01.007. PMID 17317294.
  18. ↑ 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 (2013). "Honokiol: a non-adipogenic PPARγ agonist from nature". Biochim. Biophys. Acta. 1830 (10): 4813–9. doi:10.1016/j.bbagen.2013.06.021. PMC 3790966. PMID 23811337.
  19. ↑ 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 (2013). "Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma". PLoS ONE. 8 (4): e61755. doi:10.1371/journal.pone.0061755. PMC 3632601. PMID 23630612.

External links

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