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.[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]

PPAR -alpha and -gamma pathways.

Nomenclature and tissue distribution
Peroxisome proliferator-activated receptor alpha
Identifiers
SymbolPPARA
Alt. symbolsPPAR
NCBI gene5465
HGNC9232
OMIM170998
RefSeqNM_001001928
UniProtQ07869
Other data
LocusChr. 22 q12-q13.1
Peroxisome proliferator-activated receptor gamma
Identifiers
SymbolPPARG
NCBI gene5468
HGNC9236
OMIM601487
RefSeqNM_005037
UniProtP37231
Other data
LocusChr. 3 p25
Peroxisome proliferator-activated receptor delta
Identifiers
SymbolPPARD
NCBI gene5467
HGNC9235
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, 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.[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
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  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. Bibcode:2014PLoSO...987327D. doi:10.1371/journal.pone.0087327. ISSN 1932-6203. PMC 3914821. PMID 24505284.
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  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. S2CID 3148132.
  8. Issemann I, Green S (1990). "Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators". Nature. 347 (6294): 645–50. Bibcode:1990Natur.347..645I. doi:10.1038/347645a0. PMID 2129546. S2CID 4306126.
  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.
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  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.
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