Peroxisome proliferator-activated receptor delta

2018-10-12T20:56:37Z

2600:387:3:805:0:0:0:A6: /* Knockout studies */ Fixed grammar

{{Infobox gene}}

'''Peroxisome proliferator-activated receptor beta''' or '''delta''' ('''PPAR-β''' or '''PPAR-δ'''), also known as '''NR1C2''' (nuclear receptor subfamily 1, group C, member 2) is a [[nuclear receptor]] that in humans is encoded by the ''PPARD'' [[gene]].<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>

This gene encodes a member of the peroxisome proliferator-activated receptor ([[peroxisome proliferator-activated receptor|PPAR]]) family. It was first identified in ''[[Xenopus]]'' in 1993.<ref name="pmid8274443">{{cite journal |vauthors=Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, Wahli W | title = Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids| journal = J Steroid Biochem Mol Biol | volume = 47 | issue = 1–6| pages = 65–73 | year = 1993 | pmid = 8274443 | doi = 10.1016/0960-0760(93)90058-5 }}</ref>

== Function==
PPARδ is a [[nuclear receptor|nuclear hormone receptor]] that governs a variety of biological processes and may be involved in the development of several chronic diseases, including diabetes, obesity, atherosclerosis, and cancer.<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>

In muscle PPAR-β/δ [[Gene expression|expression]] is increased by exercise, resulting in increased [[Oxidative phosphorylation|oxidative]] (fat-burning) capacity and an increase in [[Myocyte#Fiber types|type I fibers]].<ref name="pmid25945080">{{cite journal | vauthors=Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM | title=Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function | journal= NUCLEAR RECEPTOR SIGNALING | volume=13 | pages=eoo1 | year=2015 | doi= 10.1621/nrs.13001 | PMID = 25945080 | pmc=4419664 }}</ref> Both PPAR-β/δ and [[AMP-activated protein kinase|AMPK]] [[agonist]]s are regarded as exercise [[Protein mimetic|mimetics]].<ref name="pmid18674809">{{cite journal | vauthors=Giordano Attianese GM, Desvergne B | title=AMPK and PPARdelta agonists are exercise mimetics | journal= [[Cell (journal)|Cell]] | volume=134 | issue=3 | pages=405–415 | year=2008 | url=https://www.sciencedirect.com/science/article/pii/S0092867408008386 | doi= 10.1016/j.cell.2008.06.051 | PMC=2706130 | PMID = 18674809 }}</ref> In [[adipose tissue]] PPAR-β/δ increases both oxidation as well as [[Uncoupling protein|uncoupling]] of [[oxidative phosphorylation]].<ref name="pmid25945080 " />

PPARδ may function as an integrator of [[transcription (genetics)|transcription]] [[repressor|repression]] and nuclear receptor signaling. It activates transcription of a variety of target genes by binding to specific DNA elements. Well described [[:File:PPARdelta transcriptome.png|target genes of PPARδ]] include [[PDK4]], [[ANGPTL4]], [[Adipose differentiation-related protein|PLIN2]], and [[CD36]]. The expression of this gene is found to be elevated in [[colorectal cancer]] cells.<ref name="pmid16969348">{{cite journal |vauthors=Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, Xu X, Tsujino T, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M | title = Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology | journal = Br. J. Cancer | volume = 95 | issue = 7 | pages = 889–95 | year = 2006 | pmid = 16969348 | doi = 10.1038/sj.bjc.6603343 | pmc = 2360534 }}</ref> The elevated expression can be repressed by adenomatosis polyposis coli ([[APC (protein)|APC]]), a tumor suppressor protein involved in the APC/[[beta-catenin]] signaling pathway. Knockout studies in mice suggested the role of this protein in [[myelination]] of the [[corpus callosum]], [[epidermis (skin)|epidermal]] cell proliferation, and glucose<ref name="pmid16492734">{{cite journal |vauthors=Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM | title = PPARδ regulates glucose metabolism and insulin sensitivity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 9 | pages = 3444–9 | year = 2006 | pmid = 16492734 | doi = 10.1073/pnas.0511253103 | pmc = 1413918 }}</ref> and lipid metabolism.<ref>{{cite web | title = Entrez Gene: PPARD peroxisome proliferator-activated receptor delta| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5467| accessdate = }}</ref>

This protein has been shown to be involved in differentiation, lipid accumulation,<ref name="pmid15102088">{{cite journal |vauthors=Schmuth M, Haqq CM, Cairns WJ, Holder JC, Dorsam S, Chang S, Lau P, Fowler AJ, Chuang G, Moser AH, Brown BE, Mao-Qiang M, Uchida Y, Schoonjans K, Auwerx J, Chambon P, Willson TM, Elias PM, Feingold KR | title = Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes | journal = J. Invest. Dermatol. | volume = 122 | issue = 4 | pages = 971–83 |date=April 2004 | pmid = 15102088 | doi = 10.1111/j.0022-202X.2004.22412.x | url = }}</ref> directional sensing, polarization, and migration in [[keratinocyte]]s.<ref name="pmid17682064">{{cite journal |vauthors=Tan NS, Icre G, Montagner A, Bordier-ten-Heggeler B, Wahli W, Michalik L | title = The Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor β/δ Potentiates Cell Chemotactism, Polarization, and Migration | journal = Mol. Cell. Biol. | volume = 27 | issue = 20 | pages = 7161–75 |date=October 2007 | pmid = 17682064 | pmc = 2168901 | doi = 10.1128/MCB.00436-07 | url = }}</ref>

===Role in cancer===
Studies into the role of PPARδ in [[cancer]] have produced contradictory results and there is no [[scientific consensus]] on whether it promotes or prevents cancer formation.<ref name="pmid18584037">{{cite journal |vauthors=Tachibana K, Yamasaki D, Ishimoto K, Doi T | title = The Role of PPARs in Cancer | journal = PPAR Res | volume = 2008 | issue = | pages = 102737 | year = 2008 | pmid = 18584037 | pmc = 2435221 | doi = 10.1155/2008/102737 }}</ref><ref name="pmid22318237">{{cite journal |vauthors=Peters JM, Shah YM, Gonzalez FJ | title = The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention | journal = Nat. Rev. Cancer | volume = 12 | issue = 3 | pages = 181–95 |date=March 2012 | pmid = 22318237 | pmc = 3322353 | doi = 10.1038/nrc3214 }}</ref>

==Pharmacology==
Several high affinity ligands for PPARδ have been developed, including [[GW501516]] and [[GW0742]], which play an important role in research. In one study utilizing such a ligand, it has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids.<ref name="pmid16960684">{{cite journal |vauthors=Brunmair B, Staniek K, Dörig J, Szöcs Z, Stadlbauer K, Marian V, Gras F, Anderwald C, Nohl H, Waldhäusl W, Fürnsinn C | title = Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids | journal = Diabetologia | volume = 49 | issue = 11 | pages = 2713–22 |date=November 2006 | pmid = 16960684 | doi = 10.1007/s00125-006-0357-6 | url = }}</ref>

== Tissue distribution ==
PPARδ is highly expressed in many tissues, including [[Colon (anatomy)|colon]], [[small intestine]], [[liver]] and [[keratinocytes]], as well as in [[heart]], [[spleen]], [[skeletal muscle]], [[lung]], [[brain]] and [[thymus]].<ref name="pmid18442472">{{cite journal |vauthors=Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM | title = Quantitative expression patterns of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) protein in mice | journal = Biochem. Biophys. Res. Commun. | volume = 371 | issue = 3 | pages = 456–61 |date=July 2008 | pmid = 18442472 | doi = 10.1016/j.bbrc.2008.04.086 | url = | pmc = 2586836 }}</ref>

== Knockout studies==
[[Knockout mouse|Knockout mice]] lacking the ligand binding domain of PPARδ are viable. However, these mice are smaller than the wild type both [[neonatal|neo]] and [[postnatal]]ly. In addition, fat stores in the [[gonad]]s of the mutants are smaller. The mutants also display increased epidermal [[hyperplasia]] upon induction with [[12-O-Tetradecanoylphorbol-13-acetate|TPA]].<ref name="pmid 10866668">{{cite journal |vauthors=Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, Gonzalez FJ | title = Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) | volume = 20 | issue = 14 | pages = 5119–28| year = 1993 | pmid = 10866668 | journal = Mol Cell Biol | doi = 10.1128/MCB.20.14.5119-5128.2000 | pmc = 85961 }}</ref>

==Ligands==
PPARδ is activated in the cell by various fatty acids and fatty acid derivatives.<ref name="Berger_2002" /> Examples of naturally occurring fatty acids that bind with and activate PPAR delta include [[arachidonic acid]] and certain members of the [[15-hydroxyicosatetraenoic acid]] family of arachidonic acid metabolites including 15(''S'')-HETE, 15(''R'')-HETE, and 15-HpETE.<ref>Mol. Pharmacol. 77:171-184, 2010</ref> Several synthetic ligands have been identified that selectively bind PPARδ.

=== Agonists ===
* [[GW501516]]
* [[GW0742]]<ref name="pmid15604518">{{cite journal |vauthors=van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F | title = Reduced cholesterol absorption upon PPAR-δ activation coincides with decreased intestinal expression of NPC1L1 | journal = J. Lipid Res. | volume = 46 | issue = 3 | pages = 526–34 |date=March 2005 | pmid = 15604518 | doi = 10.1194/jlr.M400400-JLR200 | url = }}</ref>
* [[Telmisartan]]

==Interactions==
Peroxisome proliferator-activated receptor delta has been shown to [[Protein-protein interaction|interact]] with [[HDAC3]]<ref name="pmid12943985">{{cite journal |vauthors=Franco PJ, Li G, Wei LN | title = Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase | journal = Mol. Cell. Endocrinol. | volume = 206 | issue = 1–2 | pages = 1–12 |date=August 2003 | pmid = 12943985 | doi = 10.1016/S0303-7207(03)00254-5| url = }}</ref><ref name="pmid11867749">{{cite journal |vauthors=Shi Y, Hon M, Evans RM | title = The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 5 | pages = 2613–8 |date=March 2002 | pmid = 11867749 | pmc = 122396 | doi = 10.1073/pnas.052707099 | url = }}</ref> and [[Nuclear receptor co-repressor 2|NCOR2]].<ref name=pmid11867749/>

==References==
{{Reflist|2}}

== Further reading ==
{{refbegin | 2}}
*{{cite journal | author=Chong HC |title= Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/δ is essential for skin homeostasis and wound healing |journal= J. Cell Biol. |volume=184 |issue= 6 |pages= 817–831 |year= 2009 |pmid= 19307598 |url= http://jcb.rupress.org/content/184/6/817.long |doi= 10.1083/jcb.200809028 |name-list-format=vanc | display-authors=1 | last2=Tan | first2=M. J. | last3=Philippe | first3=V. | last4=Tan | first4=S. H. | last5=Tan | first5=C. K. | last6=Ku | first6=C. W. | last7=Goh | first7=Y. Y. | last8=Wahli | first8=W. | last9=Michalik | first9=L. | pmc=2699156}}
*{{cite journal | author=Tan NS |title= Genetic- or transforming growth factor-beta 1-induced changes in epidermal peroxisome proliferator-activated receptor beta/delta expression dictate wound repair kinetics |journal= J. Biol. Chem. |volume=280 |issue= 18 |pages= 18163–18170|year= 2005 |pmid= 15708854 |url= http://www.jbc.org/content/280/18/18163.long |doi= 10.1074/jbc.M412829200 |name-list-format=vanc | display-authors=1 | last2=Michalik | first2=L | last3=Desvergne | first3=B | last4=Wahli | first4=W}}
*{{cite journal | author=Tan NS |title= Essential role of Smad3 in the inhibition of inflammation-induced PPARβ/δ expression |journal= EMBO J. |volume= 23 |issue= 21 |pages= 4211–4221|year= 2004 |pmid= 15470497 |url= http://www.nature.com/emboj/journal/v23/n21/full/7600437a.html |doi= 10.1038/sj.emboj.7600437 |name-list-format=vanc | display-authors=1 | last2=Michalik | first2=Liliane | last3=Di-Poï | first3=Nicolas | last4=Ng | first4=Chuan Young | last5=Mermod | first5=Nicolas | last6=Roberts | first6=Anita B | last7=Desvergne | first7=Béatrice | last8=Wahli | first8=Walter | pmc=524401}}
*{{cite journal | author=Di-Poï N |title=Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway|journal= Mol. Cell |volume= 10 |issue= 4 |pages= 721–733|year= 2002 |pmid= 12419217 |url=http://www.cell.com/molecular-cell/retrieve/pii/S1097276502006469|doi=10.1016/S1097-2765(02)00646-9 | display-authors=1 | last2=Tan | first2=Nguan Soon | last3=Michalik | first3=Liliane | last4=Wahli | first4=Walter | last5=Desvergne | first5=Béatrice}}
*{{cite journal | author=Tan NS |title=Critical roles of PPARβ/δ in keratinocyte response to inflammation |journal= Genes Dev. |volume=15 |issue= 24 |pages= 3263–3277|year= 2001 |pmid= 11751632 |url=http://genesdev.cshlp.org/content/15/24/3263.long |doi=10.1101/gad.207501 |name-list-format=vanc | display-authors=1 | last2=Michalik | first2=L | last3=Noy | first3=N | last4=Yasmin | first4=R | last5=Pacot | first5=C | last6=Heim | first6=M | last7=Flühmann | first7=B | last8=Desvergne | first8=B | last9=Wahli | first9=W | pmc=312855}}
*{{cite journal | author=Michalik L |title=Impaired skin wound healing in peroxisome proliferator–activated receptor (PPAR)α and PPARβ mutant mice |journal= J. Cell Biol. |volume=154 |issue= 4 |pages= 799–814 |year= 2001 |pmid= 11514592 |url=http://jcb.rupress.org/content/154/4/799.long |doi=10.1083/jcb.200011148 |name-list-format=vanc | display-authors=1 | last2=Desvergne | first2=B | last3=Tan | first3=NS | last4=Basu-Modak | first4=S | last5=Escher | first5=P | last6=Rieusset | first6=J | last7=Peters | first7=JM | last8=Kaya | first8=G | last9=Gonzalez | first9=FJ | pmc=2196455}}
{{refend}}

== External links ==
* {{MeshName|PPAR+delta}}

{{NLM content}}
{{PDB_Gallery|geneid=5467}}
{{Transcription factors|g2}}
{{PPAR modulators}}

[[Category:Intracellular receptors]]
[[Category:Transcription factors]]
[[Category:Biology of bipolar disorder]]

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Peroxisome proliferator-activated receptor delta