Peroxisome proliferator-activated receptor delta explained

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.[1]

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

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.[3] [4]

In muscle PPARD expression is increased by exercise, resulting in increased oxidative (fat-burning) capacity and an increase in type I fibers.[5] Both PPAR-delta and AMPK agonists are regarded as exercise mimetics.[6] 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.[7] 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[8] and lipid metabolism.[9]

This protein has been shown to be involved in differentiation, lipid accumulation,[10] directional sensing, polarization, and migration in keratinocytes.[11]

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.[12] PPAR-delta favours tumour angiogenesis.[13]

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.[14]

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.[15]

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.[16] 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.[17] 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.[12]

The atypical antidepressant Tianeptine has been shown to be a high-efficacy PPAR-delta agonist. [18]

Agonists

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.[21] It and other PPAR-delta agonists are banned in sports.[22] [23]

Interactions

Peroxisome proliferator-activated receptor delta has been shown to interact with HDAC3[24] [25] and NCOR2.[25]

Further reading

Notes and References

  1. Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA . Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids . Molecular Endocrinology . 6 . 10 . 1634–1641 . October 1992 . 1333051 . 10.1210/mend.6.10.1333051 . 23506853 . free .
  2. Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, Wahli W . 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 . December 1993 . 8274443 . 10.1016/0960-0760(93)90058-5 . 25098754 .
  3. Berger J, Moller DE . The mechanisms of action of PPARs . Annual Review of Medicine . 53 . 409–435 . 2002 . 11818483 . 10.1146/annurev.med.53.082901.104018 .
  4. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W . 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 . March 2006 . 16476485 . 10.1016/j.plipres.2005.12.002 .
  5. Giordano Attianese GM, Desvergne B . Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function . Nuclear Receptor Signaling . 13 . e001 . 2015 . 25945080 . 4419664 . 10.1621/nrs.13001 .
  6. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM . AMPK and PPARdelta agonists are exercise mimetics . Cell . 134 . 3 . 405–415 . August 2008 . 18674809 . 2706130 . 10.1016/j.cell.2008.06.051 .
  7. Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, Xu X, Tsujino T, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M . Expression of PPARdelta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology . British Journal of Cancer . 95 . 7 . 889–895 . October 2006 . 16969348 . 2360534 . 10.1038/sj.bjc.6603343 .
  8. Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM . PPARdelta regulates glucose metabolism and insulin sensitivity . Proceedings of the National Academy of Sciences of the United States of America . 103 . 9 . 3444–3449 . February 2006 . 16492734 . 1413918 . 10.1073/pnas.0511253103 . free . 2006PNAS..103.3444L .
  9. Web site: Entrez Gene: PPARD peroxisome proliferator-activated receptor delta.
  10. 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 . Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes . The Journal of Investigative Dermatology . 122 . 4 . 971–983 . April 2004 . 15102088 . 10.1111/j.0022-202X.2004.22412.x . free .
  11. Tan NS, Icre G, Montagner A, Bordier-ten-Heggeler B, Wahli W, Michalik L . The nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta potentiates cell chemotactism, polarization, and migration . Molecular and Cellular Biology . 27 . 20 . 7161–7175 . October 2007 . 17682064 . 2168901 . 10.1128/MCB.00436-07 .
  12. Wagner N, Wagner KD . PPAR Beta/Delta and the Hallmarks of Cancer . Cells . 9 . 5 . 1133 . May 2020 . 32375405 . 7291220 . 10.3390/cells9051133 . free .
  13. Wagner KD, Du S, Martin L, Leccia N, Michiels JF, Wagner N . Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression . Cells . 8 . 12 . 1623 . December 2019 . 31842402 . 6952835 . 10.3390/cells8121623 . free .
  14. Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM . Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice . Biochemical and Biophysical Research Communications . 371 . 3 . 456–461 . July 2008 . 18442472 . 2586836 . 10.1016/j.bbrc.2008.04.086 .
  15. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, Gonzalez FJ . Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta) . Molecular and Cellular Biology . 20 . 14 . 5119–5128 . July 2000 . 10866668 . 85961 . 10.1128/MCB.20.14.5119-5128.2000 .
  16. Mol. Pharmacol. 77:171–184, 2010
  17. Brunmair B, Staniek K, Dörig J, Szöcs Z, Stadlbauer K, Marian V, Gras F, Anderwald C, Nohl H, Waldhäusl W, Fürnsinn C . Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids . Diabetologia . 49 . 11 . 2713–2722 . November 2006 . 16960684 . 10.1007/s00125-006-0357-6 . free .
  18. Helmstädter M, Schierle S, Isigkeit L, Proschak E, Marschner JA, Merk D . Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists . International Journal of Molecular Sciences . 23 . 17 . 10070 . September 2022 . 36077469 . 9456086 . 10.3390/ijms231710070 . free .
  19. van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F . Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1 . Journal of Lipid Research . 46 . 3 . 526–534 . March 2005 . 15604518 . 10.1194/jlr.M400400-JLR200 . 261023817 . free .
  20. Hirschfield GM, Shiffman ML, Gulamhusein A, Kowdley KV, Vierling JM, Levy C, Kremer AE, Zigmond E, Andreone P, Gordon SC, Bowlus CL, Lawitz EJ, Aspinall RJ, Pratt DS, Raikhelson K, Gonzalez-Huezo MS, Heneghan MA, Jeong SH, Ladrón de Guevara AL, Mayo MJ, Dalekos GN, Drenth JP, Janczewska E, Leggett BA, Nevens F, Vargas V, Zuckerman E, Corpechot C, Fassio E, Hinrichsen H, Invernizzi P, Trivedi PJ, Forman L, Jones DE, Ryder SD, Swain MG, Steinberg A, Boudes PF, Choi YJ, McWherter CA . Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study . Hepatology . 78 . 2 . 397–415 . August 2023 . 37386786 . 10.1097/HEP.0000000000000395 . 10344437 .
  21. News: Koh B . Anti-doping agency warns cheats on the health risks of Endurobol . 5 September 2023 . The Conversation . 22 March 2013 . en.
  22. Trevisiol S, Moulard Y, Delcourt V, Jaubert M, Boyer S, Tendon S, Haryouli H, Taleb W, Caroff M, Chabot B, Drif L, André F, Garcia P, Loup B, Popot MA, Bailly-Chouriberry L . Comprehensive characterization of the peroxisome proliferator activated receptor-δ agonist GW501516 for horse doping control analysis . Drug Testing and Analysis . 13 . 6 . 1191–1202 . June 2021 . 33547737 . 10.1002/dta.3013 . 231899376 .
  23. Sobolevsky T, Dikunets M, Sukhanova I, Virus E, Rodchenkov G . Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine . Drug Testing and Analysis . 4 . 10 . 754–760 . October 2012 . 22977012 . 10.1002/dta.1413 .
  24. Franco PJ, Li G, Wei LN . Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase . Molecular and Cellular Endocrinology . 206 . 1–2 . 1–12 . August 2003 . 12943985 . 10.1016/S0303-7207(03)00254-5 . 19487189 .
  25. Shi Y, Hon M, Evans RM . The peroxisome proliferator-activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling . Proceedings of the National Academy of Sciences of the United States of America . 99 . 5 . 2613–2618 . March 2002 . 11867749 . 122396 . 10.1073/pnas.052707099 . free . 2002PNAS...99.2613S .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Peroxisome proliferator-activated receptor delta".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.