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Peroxisome proliferator-activated receptor gamma

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Title: Peroxisome proliferator-activated receptor gamma  
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Subject: Nuclear receptor, Peroxisome proliferator-activated receptor alpha, Small heterodimer partner, Retinoid X receptor alpha, Retinoblastoma protein
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Peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma

PPAR-G dimer bound to DNA. PDB rendering based on [1].
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; CIMT1; GLM1; NR1C3; PPARG1; PPARG2; PPARgamma
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor that in humans is encoded by the PPARG gene.[2][3][4]

Contents

  • Tissue Distribution 1
  • Function 2
  • Interactions 3
  • Clinical relevance 4
  • References 5
  • Further reading 6

Tissue Distribution

PPARG, is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine).[5]

Function

PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet.[6]

This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Alternatively spliced transcript variants that encode different isoforms have been described.[7]

Interactions

Peroxisome proliferator-activated receptor gamma has been shown to interact with:

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.[18] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.[19] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.[20]

Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion. Different classes of compounds which activate PPARgamma weaker than thiazolidinediones (the so-called “partial agonists of PPARgamma”) are currently studied with the hope that such compounds would be still effective hypoglycaemic agents but with fewer side effects.[21][22] Interestingly, such partial agonists of PPARgamma are many natural compounds originating from dietary sources or from plants used in the traditional medicine.[23]

A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.[24][25]

References

  1. ^ Chandra, V.; Huang, P.; Hamuro, Y.; Raghuram, S.; Wang, Y.; Burris, T. P.; Rastinejad, F. (2008). "Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA". Nature 456 (7220): 350–356.  
  2. ^ Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD (1995). "Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping". Gene Expr. 4 (4–5): 281–99.  
  3. ^ Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J (July 1996). "Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2". Biochem. Biophys. Res. Commun. 224 (2): 431–7.  
  4. ^ Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W (December 2006). "International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors". Pharmacol. Rev. 58 (4): 726–41.  
  5. ^ Fajas L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J (July 1997). "The organization, promoter analysis, and expression of the human PPARgamma gene". J. Biol. Chem. 272 (30): 18779–89.  
  6. ^ Jones JR, Barrick C, Kim KA, Lindner J, Blondeau B, Fujimoto Y, Shiota M, Kesterson RA, Kahn BB, Magnuson MA (April 2005). "Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance". Proc. Natl. Acad. Sci. U.S.A. 102 (17): 6207–12.  
  7. ^ "Entrez Gene: PPARG peroxisome proliferator-activated receptor gamma". 
  8. ^ Brendel C, Gelman L, Auwerx J (June 2002). "Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism". Mol. Endocrinol. 16 (6): 1367–77.  
  9. ^ Berger J, Patel HV, Woods J, Hayes NS, Parent SA, Clemas J, Leibowitz MD, Elbrecht A, Rachubinski RA, Capone JP, Moller DE (April 2000). "A PPARgamma mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus". Mol. Cell. Endocrinol. 162 (1–2): 57–67.  
  10. ^ Gampe RT, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE (March 2000). "Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors". Mol. Cell 5 (3): 545–55.  
  11. ^ a b c Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J (December 2002). "The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation". Dev. Cell 3 (6): 903–10.  
  12. ^ a b c d Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S (October 2000). "Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators". J. Biol. Chem. 275 (43): 33201–4.  
  13. ^ 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.  
  14. ^ Heinlein CA, Ting HJ, Yeh S, Chang C (June 1999). "Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma". J. Biol. Chem. 274 (23): 16147–52.  
  15. ^ Nishizawa H, Yamagata K, Shimomura I, Takahashi M, Kuriyama H, Kishida K, Hotta K, Nagaretani H, Maeda N, Matsuda M, Kihara S, Nakamura T, Nishigori H, Tomura H, Moore DD, Takeda J, Funahashi T, Matsuzawa Y (January 2002). "Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation". J. Biol. Chem. 277 (2): 1586–92.  
  16. ^ Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG (November 2003). "Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha". Mol. Cell 12 (5): 1137–49.  
  17. ^ Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O'Malley B, Spiegelman BM (November 1999). "Activation of PPARgamma coactivator-1 through transcription factor docking". Science 286 (5443): 1368–71.  
  18. ^ Li Y, Qi Y, Huang TH, Yamahara J, Roufogalis BD (January 2008). "Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-alpha/-gamma activator properties". Diabetes Obes Metab 10 (1): 10–7.  
  19. ^ Hamblin M, Chang L, Fan Y, Zhang J, Chen YE (June 2009). "PPARs and the Cardiovascular System". Antioxid. Redox Signal. 11 (6): 1415–52.  
  20. ^ Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B (January 2010). "Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway". Atherosclerosis 208 (1): 119–25.  
  21. ^ Atanasov AG, Wang JN, Gu SP, Bu J, Kramer MP, Baumgartner L, Fakhrudin N, Ladurner A, Malainer C, Vuorinen A, Noha SM, Schwaiger S, Rollinger JM, Schuster D, Stuppner H, Dirsch VM, Heiss EH. "Honokiol: a non-adipogenic PPARγ agonist from nature". Biochim. Biophys. Acta 1830 (10): 4813–9.  
  22. ^ Atanasov AG, Blunder M, Fakhrudin N, Liu X, Noha SM, Malainer C, Kramer MP, Cocic A, Kunert O, Schinkovitz A, Heiss EH, Schuster D, Dirsch VM, Bauer R (2013). "Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma". PLoS ONE 8 (4): e61755.  
  23. ^ Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol. 2014 Jul 29. pii: S0006-2952(14)00424-9. doi: 10.1016/j.bcp.2014.07.018. PubMed PMID: 25083916.
  24. ^ Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA (August 2000). "PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]". Science 289 (5483): 1357–60.  
  25. ^ Chapter 20 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders.   8th edition.

Further reading

  • Qi C, Zhu Y, Reddy JK (2001). "Peroxisome proliferator-activated receptors, coactivators, and downstream targets". Cell Biochem. Biophys. 32 Spring: 187–204.  
  • Kadowaki T, Hara K, Kubota N, et al. (2002). "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance". J. Diabetes Complicat. 16 (1): 41–5.  
  • Wakino S, Law RE, Hsueh WA (2002). "Vascular protective effects by activation of nuclear receptor PPARgamma". J. Diabetes Complicat. 16 (1): 46–9.  
  • Takano H, Komuro I (2002). "Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease". J. Diabetes Complicat. 16 (1): 108–14.  
  • Stumvoll M, Häring H (2002). "The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism". Diabetes 51 (8): 2341–7.  
  • Koeffler HP (2003). "Peroxisome proliferator-activated receptor gamma and cancers". Clin. Cancer Res. 9 (1): 1–9.  
  • Puigserver P, Spiegelman BM (2003). "Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator". Endocr. Rev. 24 (1): 78–90.  
  • Takano H, Hasegawa H, Nagai T, Komuro I (2003). "The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy". Drugs Today 39 (5): 347–57.  
  • Rangwala SM, Lazar MA (2004). "Peroxisome proliferator-activated receptor gamma in diabetes and metabolism". Trends Pharmacol. Sci. 25 (6): 331–6.  
  • Cuzzocrea S (2005). "Peroxisome proliferator-activated receptors gamma ligands and ischemia and reperfusion injury". Vascul. Pharmacol. 41 (6): 187–95.  
  • Savage DB (2007). "PPAR gamma as a metabolic regulator: insights from genomics and pharmacology". Expert Reviews in Molecular Medicine 7 (1): 1–16.  
  • Pégorier JP (2005). "[PPAR receptors and insulin sensitivity: new agonists in development]". Ann. Endocrinol. (Paris) 66 (2 Pt 2): 1S10–7.  
  • Tsai YS, Maeda N (2005). "PPARgamma: a critical determinant of body fat distribution in humans and mice". Trends Cardiovasc. Med. 15 (3): 81–5.  
  • Gurnell M (2006). "Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies". Best Pract. Res. Clin. Endocrinol. Metab. 19 (4): 501–23.  
  • Cecil JE, Watt P, Palmer CN, Hetherington M (2006). "Energy balance and food intake: the role of PPARgamma gene polymorphisms". Physiol. Behav. 88 (3): 227–33.  
  • Rousseaux C, Desreumaux P (2007). "[The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)]". J. Soc. Biol. 200 (2): 121–31.  
  • Eriksson JG (2007). "Gene polymorphisms, size at birth, and the development of hypertension and type 2 diabetes". J. Nutr. 137 (4): 1063–5.  
  • Tönjes A, Stumvoll M (2007). "The role of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma in diabetes risk". Current opinion in clinical nutrition and metabolic care 10 (4): 410–4.  
  • Burgermeister E, Seger R (2007). "MAPK kinases as nucleo-cytoplasmic shuttles for PPARgamma". Cell Cycle 6 (13): 1539–48.  
  • Papageorgiou E, Pitulis N, Msaouel P, et al. (2007). "The non-genomic crosstalk between PPAR-gamma ligands and ERK1/2 in cancer cell lines". Expert Opin. Ther. Targets 11 (8): 1071–85.  

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