Biology:Peroxisome proliferator-activated receptor delta

From HandWiki
Short description: Nuclear receptor protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[5]

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.[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.[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]

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

Interactions

Peroxisome proliferator-activated receptor delta has been shown to interact with HDAC3[23][24] and NCOR2.[24]

References

  1. ↑ "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. doi:10.1210/mend.6.10.1333051. PMID 1333051. 
  2. ↑ "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. doi:10.1016/0960-0760(93)90058-5. PMID 8274443. 
  3. ↑ 3.0 3.1 "The mechanisms of action of PPARs". Annual Review of Medicine 53: 409–435. 2002. doi:10.1146/annurev.med.53.082901.104018. PMID 11818483. 
  4. ↑ "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. doi:10.1016/j.plipres.2005.12.002. PMID 16476485. 
  5. ↑ 5.0 5.1 "Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function". Nuclear Receptor Signaling 13: e001. 2015. doi:10.1621/nrs.13001. PMID 25945080. 
  6. ↑ "AMPK and PPARdelta agonists are exercise mimetics". Cell 134 (3): 405–415. August 2008. doi:10.1016/j.cell.2008.06.051. PMID 18674809. 
  7. ↑ "Expression of PPARdelta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology". British Journal of Cancer 95 (7): 889–895. October 2006. doi:10.1038/sj.bjc.6603343. PMID 16969348. 
  8. ↑ "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. doi:10.1073/pnas.0511253103. PMID 16492734. Bibcode: 2006PNAS..103.3444L. 
  9. ↑ "Entrez Gene: PPARD peroxisome proliferator-activated receptor delta". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5467. 
  10. ↑ "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. doi:10.1111/j.0022-202X.2004.22412.x. PMID 15102088. 
  11. ↑ "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. doi:10.1128/MCB.00436-07. PMID 17682064. 
  12. ↑ 12.0 12.1 "PPAR Beta/Delta and the Hallmarks of Cancer". Cells 9 (5): 1133. May 2020. doi:10.3390/cells9051133. PMID 32375405. 
  13. ↑ "Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression". Cells 8 (12): 1623. December 2019. doi:10.3390/cells8121623. PMID 31842402. 
  14. ↑ "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. doi:10.1016/j.bbrc.2008.04.086. PMID 18442472. 
  15. ↑ "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. doi:10.1128/MCB.20.14.5119-5128.2000. PMID 10866668. 
  16. ↑ Mol. Pharmacol. 77:171-184, 2010
  17. ↑ "Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids". Diabetologia 49 (11): 2713–2722. November 2006. doi:10.1007/s00125-006-0357-6. PMID 16960684. 
  18. ↑ "Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1". Journal of Lipid Research 46 (3): 526–534. March 2005. doi:10.1194/jlr.M400400-JLR200. PMID 15604518. 
  19. ↑ "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. doi:10.1097/HEP.0000000000000395. PMID 37386786. 
  20. ↑ "Anti-doping agency warns cheats on the health risks of Endurobol" (in en). The Conversation. 22 March 2013. https://theconversation.com/anti-doping-agency-warns-cheats-on-the-health-risks-of-endurobol-12997. 
  21. ↑ "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. doi:10.1002/dta.3013. PMID 33547737. 
  22. ↑ "Detection of PPARδ agonists GW1516 and GW0742 and their metabolites in human urine". Drug Testing and Analysis 4 (10): 754–760. October 2012. doi:10.1002/dta.1413. PMID 22977012. 
  23. ↑ "Interaction of nuclear receptor zinc finger DNA binding domains with histone deacetylase". Molecular and Cellular Endocrinology 206 (1–2): 1–12. August 2003. doi:10.1016/S0303-7207(03)00254-5. PMID 12943985. 
  24. ↑ 24.0 24.1 "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. doi:10.1073/pnas.052707099. PMID 11867749. Bibcode: 2002PNAS...99.2613S. 

Further reading

External links

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



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Peroxisome_proliferator-activated_receptor_delta&oldid=3598900"