DOI QR코드

DOI QR Code

TR4 Inhibits LXR-mediated Decrease of Lipid Accumulation in 3T3-L1 Adipocytes

  • Choi, Ho-Jung (Department of Biological Sciences, Chonnam National University) ;
  • Kim, Eung-Seok (Department of Biological Sciences, Chonnam National University)
  • Received : 2011.05.04
  • Accepted : 2011.06.08
  • Published : 2011.06.30

Abstract

TR4 has been suggested to play an important role in lipid metabolism in adipocytes. Although TR4 facilitates lipid accumulation during adipogenesis, the regulatory effect of TR4 on lipid storage in mature adipocytes remains unclear. We showed that TR4 inhibited the LXR agonist GW3965-mediated decrease of lipid accumulation in 3T3-L1 adipocytes. A reporter gene analysis revealed that TR4 suppressed LXR${\alpha}$ transcriptional activity, although LXR${\alpha}$ was unable to affect TR4 transcriptional activity. Moreover, adding TR4 resulted in reduced LXR${\alpha}$ binding to the LXR responsive element in a gel shift assay. Additionally, the suppressive effect of GW3965 on perilipin expression and lipid accumulation in 3T3-L1 adipocytes was abolished by TR4 overexpression. Taken together, our data demonstrate that TR4 plays an inhibitory role in LXR${\alpha}$-mediated suppression of lipid accumulation in 3T3-L1 adipocytes. This TR4 protective effect is mediated, in part, y blocking the suppressive effect of GW3965 on perilipin gene expression.

Acknowledgement

Supported by : National Research Foundation of Korea

References

  1. Apfel, R., Benbrook, D., Lernhardt, E., Ortiz, M. A., Salbert, G., and Pfahl, M. (1994) A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol. Cell. Biol. 14, 7025-7035.
  2. Brasaemle, D. L., Rubin, B., Harten, I.A., Gruia-Gray, J., Kimmel, A. R., and Londos, C. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J. Biol. Chem. 275, 38486-38493. https://doi.org/10.1074/jbc.M007322200
  3. Hashimoto, K., Ishida, E., Matsumoto, S., Okada, S., Yamada, M., Satoh, T., Monden, T., and Mori, M. (2009) Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 150, 3417-3424. https://doi.org/10.1210/en.2009-0059
  4. Hunnicutt, J. W., Hardy, R. W., Williford, J., and McDonald, J. M. (1994) Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes 43, 540-545. https://doi.org/10.2337/diabetes.43.4.540
  5. Kim, E., Liu, N. C., Yu, I. C., Lin, H. Y., Lee, Y. F., Sparks, J. D., Chen, L. M., and Chang, C. (2011a) Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-coenzyme A desaturase 1 gene expression with altered insulin sensitivity. Diabetes 60, 1493-1503. https://doi.org/10.2337/db10-0393
  6. Kim, E., Xie, S., Yeh, S. D., Lee, Y. F., Collins, L. L., Hu, Y. C., Shyr, C. R., Mu, X. M., Liu, N. C., Chen, Y. T., Wang, P. H., and Chang, C. (2003) Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster. J. Biol. Chem. 278, 46919-46926. https://doi.org/10.1074/jbc.M304088200
  7. Kim, S. J., Choi, H., Park, S. S., Chang, C., and Kim, E. (2011b) Stearoyl CoA desaturase (SCD) facilitates proliferation of prostate cancer cells through enhancement of androgen receptor transactivation. Mol. Cells 31, 371-377. https://doi.org/10.1007/s10059-011-0043-5
  8. Kim, S. J., Choi, H., Jung, C. H., Park, S. S., Cho, S. R., Oh, S., and Kim, E. (2010) Calcium mobilization inhibits lipid accumulation during the late adipogenesis via suppression of PPAR gamma and LXR alpha signalings. Korean J. Food Sci. Ani. Resour. 30, 787-794. https://doi.org/10.5851/kosfa.2010.30.5.787
  9. Lee, C. H., Chinpaisal, C., and Wei, L. N. (1998a) A novel nuclear receptor heterodimerization pathway mediated by orphan receptors TR2 and TR4. J. Biol. Chem. 273, 25209-25215. https://doi.org/10.1074/jbc.273.39.25209
  10. Lee, H. J., Lee, Y., Burbach, J. P., and Chang, C. (1995) Suppression of gene expression on the simian virus 40 major late promoter by human TR4 orphan receptor. A member of the steroid receptor superfamily. J. Biol. Chem. 270, 30129-30133. https://doi.org/10.1074/jbc.270.50.30129
  11. Lee, Y. F., Young, W. J., Burbach, J. P., and Chang, C. (1998b) Negative feedback control of the retinoid-retinoic acid/retinoid X receptor pathway by the human TR4 orphan receptor, a member of the steroid receptor superfamily. J. Biol. Chem. 273, 13437-13443. https://doi.org/10.1074/jbc.273.22.13437
  12. Lee, Y. F., Pan, H. J., Burbach, J. P., Morkin, E., and Chang, C. (1997) Identification of direct repeat 4 as a positive regulatory element for the human TR4 orphan receptor. A modulator for the thyroid hormone target genes. J. Biol. Chem. 272, 12215-12220. https://doi.org/10.1074/jbc.272.18.12215
  13. Lee, Y. F., Young, W. J., Lin, W. J., Shyr, C. R., and Chang, C. (1999) Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid hormone signaling pathways by the human TR4 orphan receptor. J. Biol. Chem. 274, 16198-16205. https://doi.org/10.1074/jbc.274.23.16198
  14. Liu, N. C., Lin, W. J., Kim, E., Collins, L. L., Lin, H. Y., Yu, I. C., Sparks, J. D., Chen, L. M., Lee, Y. F., and Chang, C. (2007) Loss of TR4 orphan nuclear receptor reduces phosphoenolpyruvate carboxykinase-mediated gluconeogenesis. Diabetes 56, 2901-2909. https://doi.org/10.2337/db07-0359
  15. Ory, D. S. (2004) Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circ. Res. 95, 660-670. https://doi.org/10.1161/01.RES.0000143422.83209.be
  16. Powell, E., Kuhn, P., and Xu, W. (2007) Nuclear Receptor Cofactors in PPAR gamma-mediated adipogenesis and adipocyte energy metabolism. PPAR Res. 2007, 53843.
  17. Reaven, G. M., Hollenbeck, C., Jeng, C. Y., Wu, M. S., and Chen, Y. D. (1988) Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 37, 1020-1024. https://doi.org/10.2337/diabetes.37.8.1020
  18. Ross, S. E., Erickson, R. L., Gerin, I., DeRose, P. M., Bajnok, L., Longo, K. A., Misek, D. E., Kuick, R., Hanash, S. M., Atkins, K. B., Andresen, S. M., Nebb, H. I., Madsen, L., Kristiansen, K., and MacDougald, O. A. (2002) Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor alpha in adipocyte metabolism. Mol. Cell Biol. 22, 5989-5999. https://doi.org/10.1128/MCB.22.16.5989-5999.2002
  19. Seo, J. B., Moon, H. M., Kim, W. S., Lee, Y. S., Jeong, H. W., Yoo, E. J., Ham, J., Kang, H., Park, M. G., Steffensen, K. R., Stulnig, T. M., Gustafsson, J. A., Park, S. D., and Kim, J. B. (2004) Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferatoractivated receptor gamma expression. Mol. Cell. Biol. 24, 3430-3444. https://doi.org/10.1128/MCB.24.8.3430-3444.2004
  20. Shyr, C. R., Hu, Y. C., Kim, E., and Chang, C. (2002) Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. J. Biol. Chem. 277, 14622-14628. https://doi.org/10.1074/jbc.M110051200
  21. Stenson, B. M., Ryden, M., Steffensen, K. R., Wahlen, K., Pettersson, A. T., Jocken, J. W., Arner, P., and Laurencikiene, J. (2009) Activation of liver X receptor regulates substrate oxidation in white adipocytes. Endocrinology 150, 4104-4113. https://doi.org/10.1210/en.2009-0676
  22. Stenson, B. M., Ryden, M., Venteclef, N., Dahlman, I., Pettersson, A. M., Mairal, A., Astrom, G., Blomqvist, L., Wang, V., Jocken, J. W., Clement, K., Langin, D., Arner, P., and Laurencikiene, J. (2011) Liver X receptor (LXR) regulates human adipocyte lipolysis. J. Biol. Chem. 286, 370-379. https://doi.org/10.1074/jbc.M110.179499
  23. Ulven, S. M., Dalen, K. T., Gustafsson, J. A., and Nebb, H. I. (2005) LXR is crucial in lipid metabolism. Prostaglandins Leukot. Essent. Fatty Acids 73, 59-63. https://doi.org/10.1016/j.plefa.2005.04.009
  24. Willy, P. J., Umesono, K., Ong, E. S., Evans, R. M., Heyman, R. A., and Mangelsdorf, D. J. (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 9, 1033-1045. https://doi.org/10.1101/gad.9.9.1033
  25. Zidi, A., Fernandez-Cabanas, V. M., Urrutia, B., Carrizosa, J., Polvillo, O., Gonzalez-Redondo, P., Jordana, J., Gallardo, D., Amills, M., and Serradilla, J. M. (2010) Association between the polymorphism of the goat stearoyl-CoA desaturase 1 (SCD1) gene and milk fatty acid composition in Murciano-Granadina goats. J. Dairy Sci. 93, 4332-4339. https://doi.org/10.3168/jds.2009-2597