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Gene Review

PPARA  -  peroxisome proliferator-activated receptor...

Homo sapiens

Synonyms: NR1C1, Nuclear receptor subfamily 1 group C member 1, PPAR, PPAR-alpha, PPARalpha, ...
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Disease relevance of PPARA

  • Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia [1].
  • Ongoing research indicates that modulation of PPAR activity might be an effective therapy for additional maladies associated with the metabolic syndrome, including obesity [2].
  • More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes [3].
  • Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases [3].
  • Activities of PPARs were assessed using JEG3 choriocarcinoma cells transfected with a PPAR-response element reporter construct (pTK-PPREx3-luc) and treated with PPAR ligands [4].

Psychiatry related information on PPARA


High impact information on PPARA


Chemical compound and disease context of PPARA


Biological context of PPARA

  • In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes [13].
  • Single Nucleotide Polymorphisms of the Peroxisome Proliferator-Activated Receptor-{alpha} Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes: The STOP-NIDDM Trial [13].
  • The lack of a detrimental effect of the null phenotype in development and reproduction opens up the possibility for null or variant PPARalpha gene (PPARA) alleles in humans [14].
  • No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected [15].
  • It was shown that a common leucine to valine (L162V) substitution at the PPARalpha gene (PPARA) is functional and affects transactivation activity of PPARalpha ligands, such as PUFA, on a concentration-dependent basis [16].

Anatomical context of PPARA

  • Here, we report for the first time that in two different human bladder cancer cell lines, RT4 (derived from grade I tumor) and T24 (derived from grade III tumor), VEGF (mRNA and protein) is differentially up-regulated by the three PPAR isotypes [17].
  • PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity [18].
  • The mRNA levels of PPAR gamma1, the predominant form in adipocytes, did not correlate with BMI, leptin mRNA levels, or fasting insulinemia in 29 subjects with various degrees of obesity [19].
  • In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I [18].
  • PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis [20].

Associations of PPARA with chemical compounds


Physical interactions of PPARA

  • All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma [18].
  • Nuclear receptor corepressor (NCoR) was demonstrated to interact strongly with peroxisome proliferator-activated receptor alpha (PPARalpha), and PPARalpha ligands suppressed this interaction [24].
  • Finally, NS 398, a COX-2 inhibitor, partially blocked the effect on PPAR activity and binding to the PPRE suggesting involvement of COX-2 metabolites in PPRE activation [25].
  • These nucleotide substitutions prevent the binding of the retinoid X receptor alpha (RXR alpha)-peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer without greatly altering the efficiency of binding of hepatocyte nuclear factor 4 (HNF4) to this recognition sequence [26].
  • Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding [27].
  • Deletion studies indicated that PPARalpha interacted with NCoR receptor-interacting domain 1 (ID1) but not ID2 or ID3 [28].

Enzymatic interactions of PPARA


Regulatory relationships of PPARA


Other interactions of PPARA


Analytical, diagnostic and therapeutic context of PPARA


  1. Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia. Eurlings, P.M., van der Kallen, C.J., Geurts, J.M., Flavell, D.M., de Bruin, T.W. Mol. Genet. Metab. (2002) [Pubmed]
  2. PPARs: therapeutic targets for metabolic disease. Berger, J.P., Akiyama, T.E., Meinke, P.T. Trends Pharmacol. Sci. (2005) [Pubmed]
  3. The mechanisms of action of PPARs. Berger, J., Moller, D.E. Annu. Rev. Med. (2002) [Pubmed]
  4. Peroxisome proliferator-activated receptor isoform expression changes in human gestational tissues with labor at term. Berry, E.B., Eykholt, R., Helliwell, R.J., Gilmour, R.S., Mitchell, M.D., Marvin, K.W. Mol. Pharmacol. (2003) [Pubmed]
  5. Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease. Brune, S., Kölsch, H., Ptok, U., Majores, M., Schulz, A., Schlosser, R., Rao, M.L., Maier, W., Heun, R. Journal of neural transmission (Vienna, Austria : 1996) (2003) [Pubmed]
  6. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Lieber, C.S. Alcohol (2004) [Pubmed]
  7. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., McKee, D.D., Galardi, C.M., Plunket, K.D., Nolte, R.T., Parks, D.J., Moore, J.T., Kliewer, S.A., Willson, T.M., Stimmel, J.B. Nature (2002) [Pubmed]
  8. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Chinetti, G., Lestavel, S., Bocher, V., Remaley, A.T., Neve, B., Torra, I.P., Teissier, E., Minnich, A., Jaye, M., Duverger, N., Brewer, H.B., Fruchart, J.C., Clavey, V., Staels, B. Nat. Med. (2001) [Pubmed]
  9. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Tontonoz, P., Singer, S., Forman, B.M., Sarraf, P., Fletcher, J.A., Fletcher, C.D., Brun, R.P., Mueller, E., Altiok, S., Oppenheim, H., Evans, R.M., Spiegelman, B.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. Babbar, N., Ignatenko, N.A., Casero, R.A., Gerner, E.W. J. Biol. Chem. (2003) [Pubmed]
  11. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. Guan, Y. J. Am. Soc. Nephrol. (2004) [Pubmed]
  12. Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma. Mössner, R., Schulz, U., Krüger, U., Middel, P., Schinner, S., Füzesi, L., Neumann, C., Reich, K. J. Invest. Dermatol. (2002) [Pubmed]
  13. Single Nucleotide Polymorphisms of the Peroxisome Proliferator-Activated Receptor-{alpha} Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes: The STOP-NIDDM Trial. Andrulionyte, L., Kuulasmaa, T., Chiasson, J.L., Laakso, M. Diabetes (2007) [Pubmed]
  14. The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants. Sapone, A., Peters, J.M., Sakai, S., Tomita, S., Papiha, S.S., Dai, R., Friedman, F.K., Gonzalez, F.J. Pharmacogenetics (2000) [Pubmed]
  15. Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. Chen, S., Tsybouleva, N., Ballantyne, C.M., Gotto, A.M., Marian, A.J. Pharmacogenetics (2004) [Pubmed]
  16. Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and apolipoprotein C-III concentrations in the Framingham Heart Study. Tai, E.S., Corella, D., Demissie, S., Cupples, L.A., Coltell, O., Schaefer, E.J., Tucker, K.L., Ordovas, J.M. J. Nutr. (2005) [Pubmed]
  17. Differential regulation of vascular endothelial growth factor expression by peroxisome proliferator-activated receptors in bladder cancer cells. Fauconnet, S., Lascombe, I., Chabannes, E., Adessi, G.L., Desvergne, B., Wahli, W., Bittard, H. J. Biol. Chem. (2002) [Pubmed]
  18. Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Fruchart, J.C., Duriez, P., Staels, B. Curr. Opin. Lipidol. (1999) [Pubmed]
  19. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Auboeuf, D., Rieusset, J., Fajas, L., Vallier, P., Frering, V., Riou, J.P., Staels, B., Auwerx, J., Laville, M., Vidal, H. Diabetes (1997) [Pubmed]
  20. The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. Vosper, H., Patel, L., Graham, T.L., Khoudoli, G.A., Hill, A., Macphee, C.H., Pinto, I., Smith, S.A., Suckling, K.E., Wolf, C.R., Palmer, C.N. J. Biol. Chem. (2001) [Pubmed]
  21. Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes. Foucher, C., Rattier, S., Flavell, D.M., Talmud, P.J., Humphries, S.E., Kastelein, J.J., Ayyobi, A., Pimstone, S., Frohlich, J., Ansquer, J.C., Steiner, G. Pharmacogenetics (2004) [Pubmed]
  22. Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study. Tai, E.S., Demissie, S., Cupples, L.A., Corella, D., Wilson, P.W., Schaefer, E.J., Ordovas, J.M. Arterioscler. Thromb. Vasc. Biol. (2002) [Pubmed]
  23. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Xu, H.E., Lambert, M.H., Montana, V.G., Plunket, K.D., Moore, L.B., Collins, J.L., Oplinger, J.A., Kliewer, S.A., Gampe, R.T., McKee, D.D., Moore, J.T., Willson, T.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. Dowell, P., Ishmael, J.E., Avram, D., Peterson, V.J., Nevrivy, D.J., Leid, M. J. Biol. Chem. (1999) [Pubmed]
  25. 85-kDa cytosolic phospholipase A2 mediates peroxisome proliferator-activated receptor gamma activation in human lung epithelial cells. Pawliczak, R., Han, C., Huang, X.L., Demetris, A.J., Shelhamer, J.H., Wu, T. J. Biol. Chem. (2002) [Pubmed]
  26. Replication of the wild type and a natural hepatitis B virus nucleocapsid promoter variant is differentially regulated by nuclear hormone receptors in cell culture. Tang, H., Raney, A.K., McLachlan, A. J. Virol. (2001) [Pubmed]
  27. Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor. Nuñez, S.B., Medin, J.A., Braissant, O., Kemp, L., Wahli, W., Ozato, K., Segars, J.H. Mol. Cell. Endocrinol. (1997) [Pubmed]
  28. A natural polymorphism in peroxisome proliferator-activated receptor-alpha hinge region attenuates transcription due to defective release of nuclear receptor corepressor from chromatin. Liu, M.H., Li, J., Shen, P., Husna, B., Tai, E.S., Yong, E.L. Mol. Endocrinol. (2008) [Pubmed]
  29. Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Lee, H., Shi, W., Tontonoz, P., Wang, S., Subbanagounder, G., Hedrick, C.C., Hama, S., Borromeo, C., Evans, R.M., Berliner, J.A., Nagy, L. Circ. Res. (2000) [Pubmed]
  30. Evidence for a new human CYP1A1 regulation pathway involving PPAR-alpha and 2 PPRE sites. Sérée, E., Villard, P.H., Pascussi, J.M., Pineau, T., Maurel, P., Nguyen, Q.B., Fallone, F., Martin, P.M., Champion, S., Lacarelle, B., Savouret, J.F., Barra, Y. Gastroenterology (2004) [Pubmed]
  31. The human peroxisome proliferator-activated receptor (PPAR) subtype NUC1 represses the activation of hPPAR alpha and thyroid hormone receptors. Jow, L., Mukherjee, R. J. Biol. Chem. (1995) [Pubmed]
  32. Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha. Combs, C.K., Bates, P., Karlo, J.C., Landreth, G.E. Neurochem. Int. (2001) [Pubmed]
  33. Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha. Jung, D., Fried, M., Kullak-Ublick, G.A. J. Biol. Chem. (2002) [Pubmed]
  34. Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Wang, X., Kilgore, M.W. Mol. Cell. Endocrinol. (2002) [Pubmed]
  35. Peroxisome proliferator-activated receptor-gamma coactivator-1 and insulin resistance: acute effect of fatty acids. Hoeks, J., Hesselink, M.K., Russell, A.P., Mensink, M., Saris, W.H., Mensink, R.P., Schrauwen, P. Diabetologia (2006) [Pubmed]
  36. Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners. Fehlberg, S., Trautwein, S., Göke, A., Göke, R. Biochem. J. (2002) [Pubmed]
  37. Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence. Ishiguro, H., Okubo, Y., Ohtsuki, T., Yamakawa-Kobayashi, K., Arinami, T. Am. J. Med. Genet. (2002) [Pubmed]
  38. Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Loviscach, M., Rehman, N., Carter, L., Mudaliar, S., Mohadeen, P., Ciaraldi, T.P., Veerkamp, J.H., Henry, R.R. Diabetologia (2000) [Pubmed]
  39. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Inoue, I., Shino, K., Noji, S., Awata, T., Katayama, S. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  40. Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas. Matthiessen, M.W., Pedersen, G., Albrektsen, T., Adamsen, S., Fleckner, J., Brynskov, J. Scand. J. Gastroenterol. (2005) [Pubmed]
  41. Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box? Molavi, B., Rasouli, N., Mehta, J.L. J. Cardiovasc. Pharmacol. Ther. (2002) [Pubmed]
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