Peroxisome proliferator-activated receptor delta

Peroxisome proliferator-activated receptor delta
PDB rendering based on 1gwx.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1GWX​, 1Y0S​, 2AWH​, 2B50​, 2BAW​, 2ENV​, 2GWX​, 2J14​, 2Q5G​, 2XYJ​, 2XYW​, 2XYX​, 2ZNP​, 2ZNQ​, 3D5F​, 3DY6​, 3ET2​, 3GWX​, 3GZ9​, 3OZ0​, 3PEQ​, 3SP9​, 3TKM​
Identifiers
Symbols	PPARD ; FAAR; NR1C2; NUC1; NUCI; NUCII; PPARB
External IDs	OMIM: 600409 MGI: 101884 HomoloGene: 4544 IUPHAR: 594 ChEMBL: 3979 GeneCards: PPARD Gene
Gene ontology Molecular function • DNA binding • transcription factor activity, sequence-specific DNA binding • steroid hormone receptor activity • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding • protein binding • drug binding • zinc ion binding • lipid binding • sequence-specific DNA binding • protein heterodimerization activity • linoleic acid binding Cellular component • nucleus • nucleoplasm Biological process • negative regulation of transcription from RNA polymerase II promoter • glucose metabolic process • generation of precursor metabolites and energy • regulation of transcription from RNA polymerase II promoter • transcription initiation from RNA polymerase II promoter • lipid metabolic process • fatty acid beta-oxidation • apoptotic process • embryo implantation • cholesterol metabolic process • cell proliferation • axon ensheathment • fatty acid catabolic process • gene expression • positive regulation of phosphatidylinositol 3-kinase signaling • regulation of satellite cell proliferation • glucose transport • fatty acid transport • cell differentiation • intracellular receptor signaling pathway • cell-substrate adhesion • wound healing • steroid hormone mediated signaling pathway • positive regulation of skeletal muscle tissue regeneration • keratinocyte proliferation • positive regulation of fat cell differentiation • negative regulation of myoblast differentiation • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • decidualization • negative regulation of epithelial cell proliferation • keratinocyte migration • adipose tissue development • cellular response to hypoxia • apoptotic signaling pathway • positive regulation of myoblast proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5467	19015
Ensembl	ENSG00000112033	ENSMUSG00000002250
UniProt	Q03181	P35396
RefSeq (mRNA)	NM_001171818	NM_011145
RefSeq (protein)	NP_001165289	NP_035275
Location (UCSC)	Chr 6: 35.34 – 35.43 Mb	Chr 17: 28.23 – 28.3 Mb
PubMed search

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.^[1]

This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) family. It was first identified in Xenopus in 1993.^[2]

Function

PPARδ is a 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.^[3][4]

PPARδ may function as an integrator of transcription repression and nuclear receptor signaling. It activates transcription of a variety of target genes by binding to specific DNA elements. Well described target genes of PPARδ include PDK4, ANGPTL4, PLIN2, and CD36. The expression of this gene is found to be elevated in colorectal cancer cells.^[5] The elevated expression can be repressed by adenomatosis polyposis coli (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, epidermal cell proliferation, and glucose^[6] and lipid metabolism.^[7]

This protein has been shown to be involved in differentiation, lipid accumulation,^[8] directional sensing, polarization, and migration in keratinocytes.^[9]

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.^[10][11]

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.^[12]

Tissue distribution

PPARδ is highly expressed in many tissues, including colon, small intestine, liver and keratinocytes, as well as in heart, spleen, skeletal muscle, lung, brain and thymus.^[13]

Knockout studies

Knockout mice lacking the ligand binding domain of PPARδ are viable. However these mice are smaller than the wild type both neo and postnatally. In addition, fat stores in the gonads of the mutants are smaller. The mutants also display increased epidermal hyperplasia upon induction with TPA.^[14]

Ligands

PPARδ is activated in the cell by various fatty acids and fatty acid derivatives.^[3] 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.^[15] Several synthetic ligands have been identified that selectively bind PPARδ.

Agonists

• GW501516
• GW0742^[16]
• Telmisartan

Interactions

Peroxisome proliferator-activated receptor delta has been shown to interact with HDAC3^[17][18] and NCOR2.^[18]

References

1. 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.
2. Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, Wahli W (1993). "Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids". J Steroid Biochem Mol Biol. 47 (1–6): 65–73. doi:10.1016/0960-0760(93)90058-5. PMID 8274443.
3. 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. (subscription required (help)).
4. 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.
5. Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, Xu X, Tsujino T, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M (2006). "Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology". Br. J. Cancer 95 (7): 889–95. doi:10.1038/sj.bjc.6603343. PMC 2360534. PMID 16969348.
6. Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM (2006). "PPARδ regulates glucose metabolism and insulin sensitivity". Proc. Natl. Acad. Sci. U.S.A. 103 (9): 3444–9. doi:10.1073/pnas.0511253103. PMC 1413918. PMID 16492734.
7. "Entrez Gene: PPARD peroxisome proliferator-activated receptor delta".
8. 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 (April 2004). "Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes". J. Invest. Dermatol. 122 (4): 971–83. doi:10.1111/j.0022-202X.2004.22412.x. PMID 15102088.
9. Tan NS, Icre G, Montagner A, Bordier-ten-Heggeler B, Wahli W, Michalik L (October 2007). "The Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor β/δ Potentiates Cell Chemotactism, Polarization, and Migration". Mol. Cell. Biol. 27 (20): 7161–75. doi:10.1128/MCB.00436-07. PMC 2168901. PMID 17682064.
10. Tachibana K, Yamasaki D, Ishimoto K, Doi T (2008). "The Role of PPARs in Cancer". PPAR Res 2008: 102737. doi:10.1155/2008/102737. PMC 2435221. PMID 18584037.
11. Peters JM, Shah YM, Gonzalez FJ (March 2012). "The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention". Nat. Rev. Cancer 12 (3): 181–95. doi:10.1038/nrc3214. PMC 3322353. PMID 22318237.
12. Brunmair B, Staniek K, Dörig J, Szöcs Z, Stadlbauer K, Marian V, Gras F, Anderwald C, Nohl H, Waldhäusl W, Fürnsinn C (November 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. PMID 16960684.
13. Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM (July 2008). "Quantitative expression patterns of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) protein in mice". Biochem. Biophys. Res. Commun. 371 (3): 456–61. doi:10.1016/j.bbrc.2008.04.086. PMC 2586836. PMID 18442472.
14. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, Gonzalez FJ. (1993). "Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ)". Mol Cell Biol. 20 (14): 5119–28. doi:10.1128/MCB.20.14.5119-5128.2000. PMC 85961. PMID 10866668.
15. Mol. Pharmacol. 77:171-184, 2010
16. van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F (March 2005). "Reduced cholesterol absorption upon PPAR-δ activation coincides with decreased intestinal expression of NPC1L1". J. Lipid Res. 46 (3): 526–34. doi:10.1194/jlr.M400400-JLR200. PMID 15604518.
17. Franco PJ, Li G, Wei LN (August 2003). "Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase". Mol. Cell. Endocrinol. 206 (1–2): 1–12. doi:10.1016/S0303-7207(03)00254-5. PMID 12943985.
18. Shi Y, Hon M, Evans RM (March 2002). "The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling". Proc. Natl. Acad. Sci. U.S.A. 99 (5): 2613–8. doi:10.1073/pnas.052707099. PMC 122396. PMID 11867749.

Further reading

• Chong HC, et al. (2009). "Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/δ is essential for skin homeostasis and wound healing". J. Cell Biol. 184 (6): 817–831. doi:10.1083/jcb.200809028. PMC 2699156. PMID 19307598.
• Tan NS, et al. (2005). "Genetic- or transforming growth factor-beta 1-induced changes in epidermal peroxisome proliferator-activated receptor beta/delta expression dictate wound repair kinetics". J. Biol. Chem. 280 (18): 18163–18170. doi:10.1074/jbc.M412829200. PMID 15708854.
• Tan NS, et al. (2004). "Essential role of Smad3 in the inhibition of inflammation-induced PPARβ/δ expression". EMBO J. 23 (21): 4211–4221. doi:10.1038/sj.emboj.7600437. PMC 524401. PMID 15470497.
• Di-Poï N; et al. (2002). "Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway". Mol. Cell 10 (4): 721–733. doi:10.1016/S1097-2765(02)00646-9. PMID 12419217.
• Tan NS, et al. (2001). "Critical roles of PPARβ/δ in keratinocyte response to inflammation". Genes Dev. 15 (24): 3263–3277. doi:10.1101/gad.207501. PMC 312855. PMID 11751632.
• Michalik L, et al. (2001). "Impaired skin wound healing in peroxisome proliferator–activated receptor (PPAR)α and PPARβ mutant mice". J. Cell Biol. 154 (4): 799–814. doi:10.1083/jcb.200011148. PMC 2196455. PMID 11514592.

External links

• PPAR delta at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.