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PPARD
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
Aliases	PPARD, FAAR, NR1C2, NUC1, NUCI, NUCII, PPARB, peroxisome proliferator activated receptor delta
External IDs	OMIM: 600409; MGI: 101884; HomoloGene: 4544; GeneCards: PPARD; OMA:PPARD - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p21.31 Start 35,342,558 bp End 35,428,191 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 A3.3|17 14.64 cM Start 28,232,700 bp End 28,301,474 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cartilage tissue skin of thigh tail of epididymis buccal mucosa cell amniotic fluid right lobe of thyroid gland left lobe of thyroid gland corpus epididymis mucosa of transverse colon placenta Top expressed in zygote lip esophagus secondary oocyte interventricular septum muscle of thigh genital tubercle colon granulocyte jejunum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sequence-specific DNA binding transcription coactivator activity zinc ion binding metal ion binding steroid hormone receptor activity fatty acid binding protein binding linoleic acid binding protein heterodimerization activity lipid binding DNA-binding transcription factor activity transcription factor binding nuclear receptor activity DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific NF-kappaB binding transcription cis-regulatory region binding RNA polymerase II transcription regulatory region sequence-specific DNA binding nuclear receptor coactivator activity signaling receptor activity Cellular component nucleoplasm nucleus RNA polymerase II transcription regulator complex Biological process fatty acid catabolic process positive regulation of myoblast proliferation positive regulation of epidermis development cell differentiation negative regulation of smooth muscle cell proliferation negative regulation of myoblast differentiation regulation of transcription, DNA-templated placenta development regulation of transcription by RNA polymerase II negative regulation of smooth muscle cell migration wound healing mRNA transcription cholesterol metabolic process negative regulation of apoptotic process response to glucose response to activity response to organic substance generation of precursor metabolites and energy regulation of fat cell differentiation transcription, DNA-templated positive regulation of transcription, DNA-templated response to vitamin A heart development cell-substrate adhesion keratinocyte proliferation positive regulation of gene expression proteoglycan metabolic process regulation of cell population proliferation negative regulation of cell growth fatty acid oxidation positive regulation of cell population proliferation glucose metabolic process phospholipid biosynthetic process negative regulation of epithelial cell proliferation positive regulation of skeletal muscle tissue regeneration apoptotic signaling pathway vitamin A metabolic process positive regulation of phosphatidylinositol 3-kinase signaling keratinocyte migration adipose tissue development transcription initiation from RNA polymerase II promoter regulation of skeletal muscle satellite cell proliferation positive regulation of fat cell differentiation negative regulation of transcription, DNA-templated negative regulation of inflammatory response cellular response to lipopolysaccharide cellular response to hypoxia negative regulation of collagen biosynthetic process positive regulation of insulin secretion steroid hormone mediated signaling pathway apoptotic process cell population proliferation negative regulation of transcription by RNA polymerase II intracellular receptor signaling pathway axon ensheathment decidualization fatty acid transport embryo implantation negative regulation of pri-miRNA transcription by RNA polymerase II lipid metabolism fatty acid beta-oxidation glucose transmembrane transport fatty acid metabolic process multicellular organism development hormone-mediated signaling pathway negative regulation of cholesterol storage regulation of lipid metabolic process response to lipid positive regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5467 19015 Ensembl ENSG00000112033 ENSMUSG00000002250 UniProt Q03181 P35396 RefSeq (mRNA) NM_001171818 NM_001171819 NM_001171820 NM_006238 NM_177435 NM_011145 RefSeq (protein) NP_001165289 NP_001165290 NP_001165291 NP_006229 NP_803184 NP_035275 Location (UCSC) Chr 6: 35.34 – 35.43 Mb Chr 17: 28.23 – 28.3 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a nuclear receptor that in humans is encoded by the PPARD gene.

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

Function

PPAR-delta 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.

In muscle PPARD expression is increased by exercise, resulting in increased oxidative (fat-burning) capacity and an increase in type I fibers. Both PPAR-delta and AMPK agonists are regarded as exercise mimetics. In adipose tissue PPAR-β/δ increases both oxidation as well as uncoupling of oxidative phosphorylation.

PPAR-delta 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. 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 and lipid metabolism.

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

Role in cancer

Studies into the role of PPAR-delta in cancer have produced contradictory results. Although there is some controversy, the majority of studies have suggested that PPAR-delta activation could result in changes that are favorable to cancer progression. PPAR-delta favours tumour angiogenesis.

Tissue distribution

PPAR-delta 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.

Knockout studies

Knockout mice lacking the ligand binding domain of PPAR-delta 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.

Ligands

PPAR-delta is activated in the cell by various fatty acids and fatty acid derivatives. 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. Several high affinity ligands for PPAR-delta 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. Initially, PPAR-delta agonists were considered promising therapies as an exercise mimetic that could treat metabolic syndrome, but later on more evidence was uncovered about their possible pro-cancer effects.

The atypical antidepressant Tianeptine has been shown to be a high-efficacy PPAR-delta agonist.

Agonists

• GW501516
• GW0742
• Seladelpar
• Telmisartan
• Tianeptine

Although its drug development was discontinued due to animal studies suggesting an increased risk of cancer, GW501516 has been used as a performance enhancing drug. It and other PPAR-delta agonists are banned in sports.

Interactions

Peroxisome proliferator-activated receptor delta has been shown to interact with HDAC3 and NCOR2.

References

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6. Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, et al. (December 1993). "Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids". The Journal of Steroid Biochemistry and Molecular Biology. 47 (1–6): 65–73. doi:10.1016/0960-0760(93)90058-5. PMID 8274443. S2CID 25098754.
7. ^ Berger J, Moller DE (2002). "The mechanisms of action of PPARs". Annual Review of Medicine. 53: 409–435. doi:10.1146/annurev.med.53.082901.104018. PMID 11818483.
8. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (March 2006). "From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions". Progress in Lipid Research. 45 (2): 120–159. doi:10.1016/j.plipres.2005.12.002. PMID 16476485.
9. ^ Giordano Attianese GM, Desvergne B (2015). "Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function". Nuclear Receptor Signaling. 13: e001. doi:10.1621/nrs.13001. PMC 4419664. PMID 25945080.
10. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. (August 2008). "AMPK and PPARdelta agonists are exercise mimetics". Cell. 134 (3): 405–415. doi:10.1016/j.cell.2008.06.051. PMC 2706130. PMID 18674809.
11. Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, Xu X, et al. (October 2006). "Expression of PPARdelta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology". British Journal of Cancer. 95 (7): 889–895. doi:10.1038/sj.bjc.6603343. PMC 2360534. PMID 16969348.
12. Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, et al. (February 2006). "PPARdelta regulates glucose metabolism and insulin sensitivity". Proceedings of the National Academy of Sciences of the United States of America. 103 (9): 3444–3449. Bibcode:2006PNAS..103.3444L. doi:10.1073/pnas.0511253103. PMC 1413918. PMID 16492734.
13. "Entrez Gene: PPARD peroxisome proliferator-activated receptor delta".
14. Schmuth M, Haqq CM, Cairns WJ, Holder JC, Dorsam S, Chang S, et al. (April 2004). "Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes". The Journal of Investigative Dermatology. 122 (4): 971–983. doi:10.1111/j.0022-202X.2004.22412.x. PMID 15102088.
15. Tan NS, Icre G, Montagner A, Bordier-ten-Heggeler B, Wahli W, Michalik L (October 2007). "The nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta potentiates cell chemotactism, polarization, and migration". Molecular and Cellular Biology. 27 (20): 7161–7175. doi:10.1128/MCB.00436-07. PMC 2168901. PMID 17682064.
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Further reading

• Chong HC, Tan MJ, Philippe V, Tan SH, Tan CK, Ku CW, et al. (March 2009). "Regulation of epithelial-mesenchymal IL-1 signaling by PPARbeta/delta is essential for skin homeostasis and wound healing". The Journal of Cell Biology. 184 (6): 817–831. doi:10.1083/jcb.200809028. PMC 2699156. PMID 19307598.
• Tan NS, Michalik L, Desvergne B, Wahli W (May 2005). "Genetic- or transforming growth factor-beta 1-induced changes in epidermal peroxisome proliferator-activated receptor beta/delta expression dictate wound repair kinetics". The Journal of Biological Chemistry. 280 (18): 18163–18170. doi:10.1074/jbc.M412829200. PMID 15708854.
• Tan NS, Michalik L, Di-Poï N, Ng CY, Mermod N, Roberts AB, et al. (October 2004). "Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression". The EMBO Journal. 23 (21): 4211–4221. doi:10.1038/sj.emboj.7600437. PMC 524401. PMID 15470497.
• Di-Poï N, Tan NS, Michalik L, Wahli W, Desvergne B (October 2002). "Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway". Molecular Cell. 10 (4): 721–733. doi:10.1016/S1097-2765(02)00646-9. PMID 12419217.
• Tan NS, Michalik L, Noy N, Yasmin R, Pacot C, Heim M, et al. (December 2001). "Critical roles of PPAR beta/delta in keratinocyte response to inflammation". Genes & Development. 15 (24): 3263–3277. doi:10.1101/gad.207501. PMC 312855. PMID 11751632.
• Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, et al. (August 2001). "Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice". The Journal of Cell Biology. 154 (4): 799–814. doi:10.1083/jcb.200011148. PMC 2196455. PMID 11514592.

External links

• PPAR+delta at the U.S. 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.

• Genes on human chromosome 6
• Intracellular receptors
• Transcription factors
• Biology of bipolar disorder