Peroxisome proliferator-activated receptor explained

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
Hgncid:	9232
Symbol:	PPARA
Altsymbols:	PPAR
Entrezgene:	5465
Omim:	170998
Refseq:	NM_001001928
Uniprot:	Q07869
Chromosome:	22
Arm:	q
Band:	12
Locussupplementarydata:	-q13.1

Peroxisome proliferator-activated receptor gamma
Hgncid:	9236
Symbol:	PPARG
Entrezgene:	5468
Omim:	601487
Refseq:	NM_005037
Uniprot:	P37231
Chromosome:	3
Arm:	p
Band:	25

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

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

• α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others^[6]
• 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.^[7] 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.^[8]

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.

After PPARδ (delta) was identified in humans in 1992,^[9] 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, whereas the use of "PPARβ" has remained in Europe, where this receptor was initially discovered in Xenopus.

PPARs were so-named because they were discovered to induce peroxisome proliferation in rodents, but this induction of peroxisome proliferation is not believed to occur in humans.^{[10] [11]}

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.^[12]

Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3. 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.^[13] 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. In addition, PPARγ was reported to be involved in cancer pathogenesis and growth.^{[14] [15]} PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.^[16] See^[17] 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 170998)
• PPARβ/δ - chromosome 6p21.2-21.1 (OMIM 600409)
• PPARγ - chromosome 3p25 (OMIM 601487).

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.^[18] 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.^[19] 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.^[20] Both natural and synthetic ligands can bind to the LBD, either activating or repressing the receptor's activity.

Pharmacology and PPAR modulators

See main article: article and PPAR modulator. PPARα and PPARγ are the molecular targets of a number of marketed drugs.

For instance the hypolipidemic fibrates activate PPARα.

The anti diabetic thiazolidinediones activate PPARγ.

The synthetic chemical perfluorooctanoic acid activates PPARα while perfluorononanoic acid activates both PPARα and PPARγ.

Berberine inactivates PPARγ.

Other natural compounds from different chemical classes activate or inactivate PPARγ.^{[21] [22] [23]}

See also

• Metabolic syndrome
• Endocannabinoid system

External links

• http://ppar.cas.psu.edu (PPAR Resource Page, Penn State University).
• http://nrresource.org (Nuclear Receptor Resource).
• PPAR reference outline (Rutgers University).
  • - the Peroxisome Proliferator-Activated Receptor Structure in Interactive 3D

Notes and 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 . International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors . Pharmacol. Rev. . 58 . 4 . 726–41 . 2006 . 17132851 . 10.1124/pr.58.4.5 . 2240461 .
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. 10.1371/journal.pone.0087327. 1932-6203. 3914821. 24505284. 2014PLoSO...987327D. free.
3. Belfiore A, Genua M, Malaguarnera R . PPAR-gamma Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer . PPAR Res . 2009 . 830501 . 2009 . 19609453 . 10.1155/2009/830501 . 2709717 . free .
4. Berger J, Moller DE . The mechanisms of action of PPARs . Annu. Rev. Med. . 53 . 409–35 . 2002 . 11818483 . 10.1146/annurev.med.53.082901.104018 .
5. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W . 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 . 2006 . 16476485 . 10.1016/j.plipres.2005.12.002 .
6. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S . The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases . J Adv Pharm Technol Res . 2 . 4 . 236–40 . October 2011 . 22247890 . 3255347 . 10.4103/2231-4040.90879 . free .
7. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W . Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors . Cell . 68 . 5 . 879–87 . 1992 . 1312391 . 10.1016/0092-8674(92)90031-7 . 3148132 .
8. Issemann I, Green S . Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators . Nature . 347 . 6294 . 645–50 . 1990 . 2129546 . 10.1038/347645a0 . 1990Natur.347..645I . 4306126 .
9. Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA . 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 . 1992 . 10.1210/mend.6.10.1333051 . 1333051 . 23506853 . free .
10. Corton JC, Peters JM, Klaunig JE . The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions . . 92 . 1 . 83–119 . 2018 . 10.1007/s00204-017-2094-7 . 6092738 . 29197930 . 2018ArTox..92...83C .
11. Book: Peroxisome Proliferator-Activated Receptors . Sugden MC, Caton PW, Holness MJ, Miller JJ . Reference Module in Life Sciences. 10.1016/B978-0-12-819460-7.00200-0. https://www.sciencedirect.com/science/article/pii/B9780128194607002000. 2021. 17. 6. 574–583 . Elsevier. 9780128096338. 241510571.
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13. Biochim. Biophys. Acta 1736:228–236, 2005
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15. Mol. Pharmacol. 77-171-184, 2010
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17. Curr. Mol. Med. 7:532–540, 2007
18. Meirhaeghe A, Amouyel P . Impact of genetic variation of PPARgamma in humans . Mol. Genet. Metab. . 83 . 1–2 . 93–102 . 2004 . 15464424 . 10.1016/j.ymgme.2004.08.014 .
19. 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 . The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity . European Journal of Human Genetics . 12 . 12 . 1050–4 . 2004 . 15367918 . 10.1038/sj.ejhg.5201283 . free .
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21. 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 . Honokiol: a non-adipogenic PPARγ agonist from nature . Biochim. Biophys. Acta . 1830 . 10 . 4813–9 . 2013 . 23811337 . 3790966 . 10.1016/j.bbagen.2013.06.021 .
22. 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 . Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma . PLOS ONE . 8 . 4 . e61755 . 2013 . 23630612 . 3632601 . 10.1371/journal.pone.0061755 . 2013PLoSO...861755A . free .
23. Ammazzalorso . Alessandra . Amoroso . Rosa . 2019-02-28 . Inhibition of PPARγ by Natural Compounds as a Promising Strategy in Obesity and Diabetes . The Open Medicinal Chemistry Journal . en . 13 . 1 . 7–15 . 10.2174/1874104501913010007. free .