User:Howard C. Berkowitz/PPAR
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that control many cellular and metabolic processes. These proteins are ligand-activated transcription factors and three isotypes called PPARa , PPARb/d and PPARg have been identified in lower vertebrates and mammals. Different drugs affect different receptors, for clinical problems such as problems of fat and cholesterol metabolism and [[diabetes mellitus#
They display differential tissue distribution and each of the three subtypes fulfills specific functions; however, all three PPARs affect energy homoeostasis and inflammatory responses. In addition, their activity can be modulated by drugs such as the hypolipidemic fibrates and the insulin sensitizing thiazolidinediones.
Thus, understanding the biology and identifying small molecule modulators of the PPARs is an active area of research and may impact chronic diseases such as diabetes, obesity, heart disease and atherosclerosis. The PPAR Resource Page (http://ppar.cas.psu.edu) is a website devoting to keeping scientists up-to-date with the latest research on these proteins and provides links to a variety of public databases. 
- 1 Wiki
- 1.1 Nomenclature and tissue distribution
- 1.2 Physiological function
- 1.3 Genetics
- 1.4 Structure
- 1.5 Pharmacology and PPAR modulators
- 1.6 See also
- 1.7 External links
- 1.8 References
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. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, and protein) of higher organisms.
Nomenclature and tissue distribution
|Locus||Chr. 22 q12-q13.1|
|Locus||Chr. 3 p25|
|Locus||Chr. 6 p21.2|
- 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 through alternative splicing is expressed in three forms:
PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes 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 sensitivity. 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, 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.
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 AGGTCAXAGGTCA, with X being a random nucleotide. In general, this sequence occurs in the promotor region of a gene, and, when the PPAR binds its ligand, transcription of targets genes are 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.
The three main forms 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 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 (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations). In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.
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. Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.
Pharmacology and PPAR modulators
PPARα and PPARγ are the molecular targets of a number of marketed drugs. The three main classes of PPAR drugs are:
PPAR-alpha is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for cholesterol disorders (generally as an adjunctive to statins) and more recently for disorders that feature high triglycerides.
PPAR-gamma is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles. Known inhibitors include the experimental agent GW-9662.
They are also used in treating hyperlipidaemia in atherosclerosis. Here they act by increasing the expression of ABCA1, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows.
A fourth class of "dual", "balanced" or "pan" PPAR ligands, which bind two or more PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome. These include the experimental compounds aleglitazar, muraglitazar and tesaglitazar. In addition, there is continuing research and development of new PPAR modulators for additional therapeutic indications.
- PPAR resource (Penn State University).
- PPAR reference outline (Rutgers University).
- Heuvel, Jack Vanden (2006), The Peroxisome Proliferator-Activated Receptor (PPAR) Resource, Center for Molecular Toxicology, Penn State University
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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. Research Blogging.
- 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". Eur. J. Hum. Genet. 12 (12): 1050–4. DOI:10.1038/sj.ejhg.5201283. PMID 15367918. Research Blogging.
- 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. Research Blogging.
- B. Brunmair et al. (2006). "Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids". Diabetologia 49 (11): 2713-22. DOI:10.1007/s00125-006-0357-6. ISSN (Print) 1432-0428 (Online) 0012-186X (Print) 1432-0428 (Online). Research Blogging.
- Fiévet C, Fruchart JC, Staels B (2006). "PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome". Current opinion in pharmacology 6 (6): 606–14. DOI:10.1016/j.coph.2006.06.009. PMID 16973418. Research Blogging.
- Balakumar P, Rose M, Ganti SS, Krishan P, Singh M (2007). "PPAR dual agonists: are they opening Pandora's Box?". Pharmacol. Res. 56 (2): 91–8. DOI:10.1016/j.phrs.2007.03.002. PMID 17428674. Research Blogging.
- Staels B, Fruchart JC (2005). "Therapeutic roles of peroxisome proliferator-activated receptor agonists". Diabetes 54 (8): 2460-70. DOI:10.2337/diabetes.54.8.2460. PMID 16046315. Research Blogging.