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Gene Review

PPARGC1A  -  peroxisome proliferator-activated receptor...

Homo sapiens

Synonyms: LEM6, Ligand effect modulator 6, PGC-1(alpha), PGC-1-alpha, PGC-1v, ...
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Disease relevance of PPARGC1A

  • Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men [1].
  • In this study, we examined whether the PPARGC1A gene locus is associated with type 2 diabetes mellitus [2].
  • CONCLUSIONS/INTERPRETATION: Our findings confirm that sex and age should be considered when investigating the influence of the PPARGC1A Gly482Ser polymorphism on metabolic disease [1].
  • We therefore ascertained associations of PPARGC1A polymorphisms with asymptomatic carotid atherosclerosis [3].
  • The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004) [4].

Psychiatry related information on PPARGC1A

  • Whenever possible, the level of physical activity should be addressed in future studies on disease risk associated with PPARGC1A Gly482Ser [1].

High impact information on PPARGC1A

  • Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators [5].
  • Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1 [6].
  • Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration [7].
  • One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family [7].
  • Once PGC-1 alpha is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver [8].

Chemical compound and disease context of PPARGC1A

  • These data suggest that increased PGC-1 expression and subsequent hepatic glucose production contribute to the insulin resistance observed in the IUGR juvenile rat [9].
  • CONCLUSION: These findings suggest that PGC-1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators [10].

Biological context of PPARGC1A


Anatomical context of PPARGC1A


Associations of PPARGC1A with chemical compounds

  • Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes [11].
  • Finally, PERC enhances the ERalpha-mediated response to the partial agonist tamoxifen, while PGC-1 modestly represses it [16].
  • Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1 alpha were required for full activation of CAR [17].
  • A single nucleotide polymorphism within the coding region of the PGC-1 gene predicts a glycine to serine substitution at amino acid 482 and has been associated with type 2 diabetes in a Danish population [18].
  • As in rodents, PGC-1 is involved in the transcriptional regulation of the UCP1 gene in humans and mediates the effects of PPARalpha and PPARgamma agonists and retinoic acid [14].
  • We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors [19].

Physical interactions of PPARGC1A

  • Second, PGC-1 interacts physically with ERRalpha and enables it to activate transcription [20].

Regulatory relationships of PPARGC1A


Other interactions of PPARGC1A


Analytical, diagnostic and therapeutic context of PPARGC1A

  • PPARGC1A/B mRNA was quantified by RT-PCR [26].
  • CONCLUSIONS/INTERPRETATION: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk [27].
  • CONCLUSIONS/INTERPRETATION: Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents [28].
  • An immunoprecipitation assay reveals that PGC-1 and RXRalpha interact in vivo [29].
  • We demonstrate further, in a mammalian two-hybrid assay, that this physical interaction also requires the presence of the AF-2 region of RXR to interact with the LXXLL motif of PGC-1, which is consistent with our protein-protein interaction results [29].


  1. Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men. Ridderstråle, M., Johansson, L.E., Rastam, L., Lindblad, U. Diabetologia (2006) [Pubmed]
  2. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha promoter polymorphisms are associated with early-onset type 2 diabetes mellitus in the Korean population. Kim, J.H., Shin, H.D., Park, B.L., Cho, Y.M., Kim, S.Y., Lee, H.K., Park, K.S. Diabetologia (2005) [Pubmed]
  3. Associations of PPARGC1A haplotypes with plaque score but not with intima-media thickness of carotid arteries in middle-aged subjects. Iglseder, B., Oberkofler, H., Felder, T.K., Klein, K., Paulweber, B., Krempler, F., Tregouet, D.A., Patsch, W. Stroke (2006) [Pubmed]
  4. Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer. Wirtenberger, M., Tchatchou, S., Hemminki, K., Schmutzhard, J., Sutter, C., Schmutzler, R.K., Meindl, A., Wappenschmidt, B., Kiechle, M., Arnold, N., Weber, B.H., Niederacher, D., Bartram, C.R., Burwinkel, B. Carcinogenesis (2006) [Pubmed]
  5. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J.M., Rhee, J., J??ger, S., Handschin, C., Zheng, K., Lin, J., Yang, W., Simon, D.K., Bachoo, R., Spiegelman, B.M. Cell (2006) [Pubmed]
  6. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R.C., Spiegelman, B.M. Cell (1999) [Pubmed]
  7. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Handschin, C., Spiegelman, B.M. Endocr. Rev. (2006) [Pubmed]
  8. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Puigserver, P., Spiegelman, B.M. Endocr. Rev. (2003) [Pubmed]
  9. Increased hepatic peroxisome proliferator-activated receptor-gamma coactivator-1 gene expression in a rat model of intrauterine growth retardation and subsequent insulin resistance. Lane, R.H., MacLennan, N.K., Hsu, J.L., Janke, S.M., Pham, T.D. Endocrinology (2002) [Pubmed]
  10. Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis. Bertolotti, M., Gabbi, C., Anzivino, C., Mitro, N., Godio, C., De Fabiani, E., Crestani, M., Del Puppo, M., Ricchi, M., Carulli, L., Rossi, A., Loria, P., Carulli, N. Eur. J. Clin. Invest. (2006) [Pubmed]
  11. Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes. Pihlajamäki, J., Kinnunen, M., Ruotsalainen, E., Salmenniemi, U., Vauhkonen, I., Kuulasmaa, T., Kainulainen, S., Laakso, M. Diabetologia (2005) [Pubmed]
  12. Discordant gene expression in skeletal muscle and adipose tissue of patients with type 2 diabetes: effect of interleukin-6 infusion. Carey, A.L., Petersen, E.W., Bruce, C.R., Southgate, R.J., Pilegaard, H., Hawley, J.A., Pedersen, B.K., Febbraio, M.A. Diabetologia (2006) [Pubmed]
  13. 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]
  14. Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity. Oberkofler, H., Esterbauer, H., Linnemayr, V., Strosberg, A.D., Krempler, F., Patsch, W. J. Biol. Chem. (2002) [Pubmed]
  15. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Russell, A.P., Feilchenfeldt, J., Schreiber, S., Praz, M., Crettenand, A., Gobelet, C., Meier, C.A., Bell, D.R., Kralli, A., Giacobino, J.P., Dériaz, O. Diabetes (2003) [Pubmed]
  16. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha. Kressler, D., Schreiber, S.N., Knutti, D., Kralli, A. J. Biol. Chem. (2002) [Pubmed]
  17. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state. Shiraki, T., Sakai, N., Kanaya, E., Jingami, H. J. Biol. Chem. (2003) [Pubmed]
  18. A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians. Muller, Y.L., Bogardus, C., Pedersen, O., Baier, L. Diabetes (2003) [Pubmed]
  19. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Ling, C., Del Guerra, S., Lupi, R., Rönn, T., Granhall, C., Luthman, H., Masiello, P., Marchetti, P., Groop, L., Del Prato, S. Diabetologia (2008) [Pubmed]
  20. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). Schreiber, S.N., Knutti, D., Brogli, K., Uhlmann, T., Kralli, A. J. Biol. Chem. (2003) [Pubmed]
  21. Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Daitoku, H., Yamagata, K., Matsuzaki, H., Hatta, M., Fukamizu, A. Diabetes (2003) [Pubmed]
  22. An intronic peroxisome proliferator-activated receptor-binding sequence mediates fatty acid induction of the human carnitine palmitoyltransferase 1A. Napal, L., Marrero, P.F., Haro, D. J. Mol. Biol. (2005) [Pubmed]
  23. Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor. Knutti, D., Kressler, D., Kralli, A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. The gene expression profile of extraskeletal myxoid chondrosarcoma. Subramanian, S., West, R.B., Marinelli, R.J., Nielsen, T.O., Rubin, B.P., Goldblum, J.R., Patel, R.M., Zhu, S., Montgomery, K., Ng, T.L., Corless, C.L., Heinrich, M.C., van de Rijn, M. J. Pathol. (2005) [Pubmed]
  25. Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. Hammarstedt, A., Jansson, P.A., Wesslau, C., Yang, X., Smith, U. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  26. Fatty acid-induced differential regulation of the genes encoding peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in human skeletal muscle cells that have been differentiated in vitro. Staiger, H., Staiger, K., Haas, C., Weisser, M., Machicao, F., Häring, H.U. Diabetologia (2005) [Pubmed]
  27. Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Barroso, I., Luan, J., Sandhu, M.S., Franks, P.W., Crowley, V., Schafer, A.J., O'rahilly, S., Wareham, N.J. Diabetologia (2006) [Pubmed]
  28. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1. Al-Khalili, L., Forsgren, M., Kannisto, K., Zierath, J.R., Lönnqvist, F., Krook, A. Diabetologia (2005) [Pubmed]
  29. PGC-1 functions as a transcriptional coactivator for the retinoid X receptors. Delerive, P., Wu, Y., Burris, T.P., Chin, W.W., Suen, C.S. J. Biol. Chem. (2002) [Pubmed]
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