| Written | 2009-06 | Erhan Astarci, Sreeparna Banerjee |
| Department of Biology, Middle East Technical University, Ankara 06531, Turkey |
| Identity |
| Alias_names | peroxisome proliferative activated receptor, delta |
| peroxisome proliferator-activated receptor delta | |
| Alias_symbol (synonym) | NUC1 |
| NUCII | |
| FAAR | |
| NR1C2 | |
| Other alias | MGC3931 |
| NUCI | |
| PPAR-beta | |
| PPAR-delta | |
| PPARB | |
| HGNC (Hugo) | PPARD |
| LocusID (NCBI) | 5467 |
| Atlas_Id | 41794 |
| Location | 6p21.31 [Link to chromosome band 6p21] |
| Location_base_pair | Starts at 35342558 and ends at 35428191 bp from pter ( according to hg19-Feb_2009) [Mapping PPARD.png] |
| Local_order | According to NCBI Map Viewer, genes flanking PPAR delta in centromere to telomere direction on 6p21 are: - UHRF1BP1 (UHRF1 (ICBP90) binding protein 1) - ZNF76 (zinc finger protein 76 (expressed in testis)) - DEF6 (differentially expressed in FDCP 6 homolog (mouse)) - PPARD (peroxisome proliferator-activated receptor delta) - TULP1 (tubby like protein 1) - C6orf126 (chromosome 6 open reading frame 126) |
| Fusion genes (updated 2016) | DEF6 (6p21.31) / PPARD (6p21.31) | PPARD (6p21.31) / ARHGEF1 (19q13.2) | PPARD (6p21.31) / PPARD (6p21.31) |
| PPARD (6p21.31) / TMEM2 (9q21.13) | PPARD (6p21.31) / WNK4 (17q21.31) |
| Note | PPAR delta is one of the orphan nuclear hormone receptors which were first identified as proteins that control the size and the numbers of peroxisomes by binding to the peroxisome proliferators. PPARs (classified as PPARalpha, PPARgamma and delta/beta) perform a number of functions and are implicated in several diseases such as obesity, diabetes, cancer and atherosclerosis. In comparison to the other peroxisome proliferators, PPAR delta protein is a potent inhibitor of PPAR alpha and PPAR gamma and this phenomenon is ligand induced. |
| DNA/RNA |
| Note | PPAR delta gene is located on chromosome 6p21-22. |
 | |
| PPAR delta gene diagram. Red boxes indicate the exons. Start and stop codons are shown by the two arrows respectively. | |
| Description | According to Entrez-Gene, PPARD gene maps to NC_000006.10 and spans a region of 10.7 kilo bases. According to Spidey (mRNA to genomic sequence alignment tool), PPAR delta has 8 exons, the sizes being 124, 84, 231, 155, 139, 203, 451, 2347. |
| Transcription | PPAR delta mRNA NM_006238 has 3734 bp. PPAR-delta is activated by either hypolipidemic drugs or fatty acids. The mammalian counterparts are particularly activated by 18C unsaturated fatty acids. According to GeneCards, PPAR delta expression was detected in 12 human tissues including spleen, thymus, brain, spinal cord, heart, skeletal cord, liver, pancreas, prostate, kidney and lung. |
| Pseudogene | According to Entrez Gene, ppar delta (PPARD) has no known pseudogenes. |
| Protein |
| Note | PPARD has two protein isoforms produced by alternative splicing. PPAR delta acts as a transcription factor in the presence of a ligand and after heterodimerization with the retinoid acid X receptor. |
| Description | PPARD protein is composed of 441 amino acids and has a molecular weight of 49.9 kDa. According to the NCBI conserved domain search, the protein contains two zinc finger C4 type domains which is a conserved domain in proteins with DNA binding activity. The protein also has a flexible hinge region and a ligand binding domain near the C terminus. |
| Expression | PPAR delta is expressed in wide range of tissues and is highly expressed in spleen, thymus, brain, spinal cord, heart, skeletal cord, liver, pancreas, prostate, kidney and lung. |
| Localisation | Located in the nucleus. |
| Function | Similar to other peroxisome proliferator activated receptors PPAR delta is also involved in differentiation and metabolism. Fatty acid regulation and oxidation in skeletal muscle and adipose tissues is one of the major functions of PPAR delta. It has been shown that the increase in muscle oxidative capacity correlates positively with PPAR delta expression. Additionally, fatty acid efflux is also regulated by PPAR delta by redirection of the fatty acid ligand from the adipose tissue to the skeletal muscles which results in a decrease in the size of the adipose tissue. Fatty acids are natural ligands of the PPAR delta and it is known that its activity increases by certain eicosanoids like leukotriene B4. |
| Homology | Canis familiaris: PPAR-beta, peroxisome proliferator-activated receptor delta. Pan troglodytes: LOC463188, peroxisome proliferator-activated receptor delta. Rattus norvegicus: Ppard, peroxisome proliferator activated receptor delta. Mus musculus: Ppard, peroxisome proliferator activator receptor delta. Gallus gallus: PPARD, peroxisome proliferator-activated receptor delta. |
| Mutations |
| Note | SNP rs1053049 rs6902123 rs2267668 are associated with insulin resistance. SNP rs2016520, rs3734254 and rs9794 are associated with obesity. Gly482Ser is associated with insulin resistance. -87T/C polymorphism is associated with alterations in cholesterol metabolism. -13454G>T, c.2022+12G>A, c.2629T>C, c.2806C>G are associated with obesity. |
| Implicated in |
| Note | |
| Entity | Colorectal cancer |
| Disease | PPARdelta is overexpressed in human colon cancers and genetic disruption of the gene in mice was shown to significantly reduce the incidence of colorectal cancer by reducing expression of vascular endothelial growth factor. Additionally, Wnt/beta-catenin has been shown to stimulate PPAR delta expression. Activation of the COX-2 pathway resulting in the production of prostaglandin E2 activated PPAR delta via the PI3K-Akt pathway. PPAR delta can also cross talk with other transcription factors such as nuclear factor kappa B. PPAR delta is highly expressed in the gastrointestinal tract in a constitutive manner where it regulates cell proliferation and differentiation. In mouse it has been shown that mouse PPAR delta has both ligand dependent and independent effects and ligand independent effects are involved in down regulation of inflammation whereas the ligand dependent effects include proliferation and differentiation. Contradicting results support that PPARdelta can induce or alleviate the disease progression. |
| Entity | Insulin resistance |
| Disease | Single nucleotide polymorphisms (SNPs) in the PPAR delta gene are associated with insulin resistance and increased fat storage due to an interference in mitochondrial functions. After having genotyped 156 patients for the reference SNPs (rs) who are in the risk group for type 2 diabetes, they were shown to carry the SNPs rs1053049, rs6902123, and rs2267668 (A:A, A:G, A:G respectively) in the PPAR delta gene. Another study indicated that a (-87 T/C) polymorphism affects both plasma glucose levels in the fasting state, insulin sensitivity and cholesterol metabolism. Carriers with the C allele displayed increased plasma glucose levels and decreased insulin sensitivity with respect to the T allele carrying counterparts. Higher titer of low density lipoprotein was also observed in the C allele carriers. It was also concluded that higher levels of fasting plasma glucose levels were independent from the etiology of being diabetic or glucose tolerant. In both cases, insulin sensitivity was disrupted. |
| Entity | Obesity |
| Disease | Catabolism of fats has been shown to be regulated by PPAR delta which could thus be exploited as a potential target for the treatment of obesity and type-2 diabetes. Of the nine polymorphic markers sequenced in the PPAR delta gene four polymorphisms were found in the intronic regions, one in an untranslated region and four in the 3' untranslated region (UTR). The polymorphisms were -13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G. The same polymorphisms, however, were not significantly associated with the risk for Type 2 diabetes. However in terms of fasting plasma glucose levels and body mass index, the findings were found to be associated with obesity. |
| Entity | Atherosclerosis |
| Disease | As lipid metabolism is involved in atherogenesis, the effects PPARdelta expression in atherosclerotic changes in macrophages were investigated. It has been shown that use of PPAR delta agonists reduces atherosclerosis in apoE double negative mice. The mechanism has been shown to be through elevation of high density lipoprotein level and suppression of inflammation possibly by the down regulation of chemokines which then results in a decrease in the chemoattractant signaling. PPARdelta activation is also associated with the increased expression of G-protein signaling genes which has been shown to block the chemokine receptors. |
| Bibliography |
| PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. |
| Barish GD, Atkins AR, Downes M, Olson P, Chong LW, Nelson M, Zou Y, Hwang H, Kang H, Curtiss L, Evans RM, Lee CH. |
| Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4271-6. Epub 2008 Mar 12. |
| PMID 18337509 |
| Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. |
| Chen S, Tsybouleva N, Ballantyne CM, Gotto AM Jr, Marian AJ. |
| Pharmacogenetics. 2004 Jan;14(1):61-71. |
| PMID 15128052 |
| PPARs: the vasculature, inflammation and hypertension. |
| Duan SZ, Usher MG, Mortensen RM. |
| Curr Opin Nephrol Hypertens. 2009 Mar;18(2):128-33. |
| PMID 19434050 |
| Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice. |
| Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM. |
| Biochem Biophys Res Commun. 2008 Jul 4;371(3):456-61. Epub 2008 Apr 28. |
| PMID 18442472 |
| Peroxisome proliferator-activated receptor (PPAR) delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects. |
| Hu C, Jia W, Fang Q, Zhang R, Wang C, Lu J, Xiang K. |
| Diabet Med. 2006 Dec;23(12):1307-12. |
| PMID 17116180 |
| Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. |
| Jiang WG, Watkins G, Douglas-Jones A, Mansel RE. |
| Prostaglandins Leukot Essent Fatty Acids. 2006 Apr;74(4):235-45. Epub 2006 Mar 23. |
| PMID 16556493 |
| PPARbeta/delta ligands as modulators of the inflammatory response. |
| Kilgore KS, Billin AN. |
| Curr Opin Investig Drugs. 2008 May;9(5):463-9. (REVIEW) |
| PMID 18465655 |
| Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. |
| Marin HE, Peraza MA, Billin AN, Willson TM, Ward JM, Kennett MJ, Gonzalez FJ, Peters JM. |
| Cancer Res. 2006 Apr 15;66(8):4394-401. |
| PMID 16618765 |
| NO-donating aspirin isomers downregulate peroxisome proliferator-activated receptor (PPAR)delta expression in APC(min/+) mice proportionally to their tumor inhibitory effect: Implications for the role of PPARdelta in carcinogenesis. |
| Ouyang N, Williams JL, Rigas B. |
| Carcinogenesis. 2006 Feb;27(2):232-9. Epub 2005 Sep 1. |
| PMID 16141240 |
| Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. |
| Peters JM, Hollingshead HE, Gonzalez FJ. |
| Clin Sci (Lond). 2008 Aug;115(4):107-27. (REVIEW) |
| PMID 18616431 |
| Activation of PPAR{beta}/{delta} inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release. |
| Piqueras L, Sanz MJ, Perretti M, Morcillo E, Norling L, Mitchell JA, Li Y, Bishop-Bailey D. |
| J Leukoc Biol. 2009 Apr 23. [Epub ahead of print] |
| PMID 19389799 |
| Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity. |
| Shin HD, Park BL, Kim LH, Jung HS, Cho YM, Moon MK, Park YJ, Lee HK, Park KS. |
| Diabetes. 2004 Mar;53(3):847-51. |
| PMID 14988273 |
| Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention. |
| Stefan N, Thamer C, Staiger H, Machicao F, Machann J, Schick F, Venter C, Niess A, Laakso M, Fritsche A, Haring HU. |
| J Clin Endocrinol Metab. 2007 May;92(5):1827-33. Epub 2007 Feb 27. |
| PMID 17327385 |
| Variations in PPARD determine the change in body composition during lifestyle intervention: a whole-body magnetic resonance study. |
| Thamer C, Machann J, Stefan N, Schafer SA, Machicao F, Staiger H, Laakso M, Bottcher M, Claussen C, Schick F, Fritsche A, Haring HU. |
| J Clin Endocrinol Metab. 2008 Apr;93(4):1497-500. Epub 2008 Feb 5. |
| PMID 18252792 |
| A gut feeling of the PXR, PPAR and NF-kappaB connection. |
| Wahli W. |
| J Intern Med. 2008 Jun;263(6):613-9. (REVIEW) |
| PMID 18479261 |
| The PPAR-gamma Agonist 15-Deoxy-Delta-Prostaglandin J(2) Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer's Disease. |
| Xu J, Barger SW, Drew PD. |
| PPAR Res. 2008;2008:349185. |
| PMID 18615183 |
| Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis. |
| Zuo X, Peng Z, Moussalli MJ, Morris JS, Broaddus RR, Fischer SM, Shureiqi I. |
| J Natl Cancer Inst. 2009 May 20;101(10):762-7. Epub 2009 May 12. |
| PMID 19436036 |
| Citation |
| This paper should be referenced as such : |
| Astarci, E ; Banerjee, S |
| PPARD (peroxisome proliferator-activated receptor delta) |
| Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):470-472. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/PPARDID41794ch6p21.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Sep 18 17:11:44 CEST 2017 |
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