DOI QR코드

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Retinoid X Receptor α Overexpression Alleviates Mitochondrial Dysfunction-induced Insulin Resistance through Transcriptional Regulation of Insulin Receptor Substrate 1

  • Lee, Seung Eun (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Koo, Young Do (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Lee, Ji Seon (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Kwak, Soo Heon (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Jung, Hye Seung (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Cho, Young Min (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Park, Young Joo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Chung, Sung Soo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Park, Kyong Soo (Department of Internal Medicine, Seoul National University College of Medicine)
  • 투고 : 2014.10.17
  • 심사 : 2014.12.22
  • 발행 : 2015.04.30

초록

Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor ${\alpha}$ ($RXR{\alpha}$) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether $RXR{\alpha}$ activation or overexpression can restore IRS1 expression. Both IRS1 and $RXR{\alpha}$ protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of $RXR{\alpha}$ agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. $RXR{\alpha}$ overexpression also increased IRS1 transcription and mitochondrial function. Because $RXR{\alpha}$ overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that $RXR{\alpha}$ directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that $RXR{\alpha}$ bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor ${\delta}$ ($PPAR{\delta}$). These results suggest that $RXR{\alpha}$ overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

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참고문헌

  1. Anderson, E.J., Lustig, M.E., Boyle, K.E., Woodlief, T.L., Kane, D.A., Lin, C.T., Price, J.W., 3rd, Kang, L., Rabinovitch, P.S., Szeto, H.H., et al. (2009). Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Invest. 119, 573-581. https://doi.org/10.1172/JCI37048
  2. Cesario, R.M., Klausing, K., Razzaghi, H., Crombie, D., Rungta, D., Heyman, R.A., and Lala, D.S. (2001). The rexinoid LG100754 is a novel RXR:PPARgamma agonist and decreases glucose levels in vivo. Mol. Endocrinol. 15, 1360-1369.
  3. Chae, S., Ahn, B.Y., Byun, K., Cho, Y.M., Yu, M.H., Lee, B., Hwang, D., and Park, K.S. (2013). A systems approach for decoding mitochondrial retrograde signaling pathways. Sci. Signal. 6, rs4.
  4. Egawa, K., Nakashima, N., Sharma, P.M., Maegawa, H., Nagai, Y., Kashiwagi, A., Kikkawa, R., and Olefsky, J.M. (2000). Persistent activation of phosphatidylinositol 3-kinase causes insulin resistance due to accelerated insulin-induced insulin receptor substrate-1 degradation in 3T3-L1 adipocytes. Endocrinology 141, 1930-1935. https://doi.org/10.1210/endo.141.6.7516
  5. Evans, R.M., and Mangelsdorf, D.J. (2014). Nuclear receptors, RXR, and the big bang. Cell 157, 255-266. https://doi.org/10.1016/j.cell.2014.03.012
  6. Fisher-Wellman, K.H., and Neufer, P.D. (2012). Linking mitohondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol. Metab. 23, 142-153. https://doi.org/10.1016/j.tem.2011.12.008
  7. Gianni, M., Tarrade, A., Nigro, E.A., Garattini, E., and Rochette-Egly, C. (2003). The AF-1 and AF-2 domains of RAR gamma 2 and RXR alpha cooperate for triggering the transactivation and the degradation of RAR gamma 2/RXR alpha heterodimers. J. Biol. Chem. 278, 34458-34466. https://doi.org/10.1074/jbc.M304952200
  8. Gual, P., Le Marchand-Brustel, Y., and Tanti, J.F. (2005). Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87, 99-109. https://doi.org/10.1016/j.biochi.2004.10.019
  9. Heyman, R.A., Mangelsdorf, D.J., Dyck, J.A., Stein, R.B., Eichele, G., Evans, R.M., and Thaller, C. (1992). 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68, 397-406. https://doi.org/10.1016/0092-8674(92)90479-V
  10. Kelley, D.E., He, J., Menshikova, E.V., and Ritov, V.B. (2002). Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944-2950. https://doi.org/10.2337/diabetes.51.10.2944
  11. Kelley, D.E., and Simoneau, J.A. (1994). Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J. Clin. Invest. 94, 2349-2356. https://doi.org/10.1172/JCI117600
  12. Kim, M., Ahn, B.Y., Lee, J.S., Chung, S.S., Lim, S., Park, S.G., Jung, H.S., Lee, H.K., and Park, K.S. (2009). The ginsenoside Rg3 has a stimulatory effect on insulin signaling in L6 myotubes. Biochem. Biophys. Res. Commun. 389, 70-73. https://doi.org/10.1016/j.bbrc.2009.08.088
  13. Kliewer, S.A., Umesono, K., Noonan, D.J., Heyman, R.A., and Evans, R.M. (1992). Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358, 771-774. https://doi.org/10.1038/358771a0
  14. Leibowitz, M.D., Ardecky, R.J., Boehm, M.F., Broderick, C.L., Caragna, M.A., Crombie, D.L., D'Arrigo, J., Etgen, G.J., Faul, M.M., Grese, T.A., et al. (2006). Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes. Endocrinology 147, 1044-1053. https://doi.org/10.1210/en.2005-0690
  15. Lenhard, J.M., Lancaster, M.E., Paulik, M.A., Weiel, J.E., Binz, J.G., Sundseth, S.S., Gaskill, B.A., Lightfoot, R.M., and Brown, H.R. (1999). The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction. Diabetologia 42, 545-554. https://doi.org/10.1007/s001250051193
  16. Lowell, B.B., and Shulman, G.I. (2005). Mitochondrial dysfunction and type 2 diabetes. Science 307, 384-387. https://doi.org/10.1126/science.1104343
  17. Macotela, Y., Emanuelli, B., Bang, A.M., Espinoza, D.O., Boucher, J., Beebe, K., Gall, W., and Kahn, C.R. (2011). Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6, e21187. https://doi.org/10.1371/journal.pone.0021187
  18. Martin, S.D., and McGee, S.L. (2014). The role of mitochondria in the aetiology of insulin resistance and type 2 diabetes. Biochim. Biophys. Acta 1840, 1303-1312. https://doi.org/10.1016/j.bbagen.2013.09.019
  19. Morino, K., Petersen, K.F., Dufour, S., Befroy, D., Frattini, J., Shatzkes, N., Neschen, S., White, M.F., Bilz, S., Sono, S., et al. (2005). Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115, 3587-3593. https://doi.org/10.1172/JCI25151
  20. Osburn, D.L., Shao, G., Seidel, H.M., and Schulman, I.G. (2001). Ligand-dependent degradation of retinoid X receptors does not require transcriptional activity or coactivator interactions. Mol. Cell. Biol. 21, 4909-4918. https://doi.org/10.1128/MCB.21.15.4909-4918.2001
  21. Pederson, T.M., Kramer, D.L., and Rondinone, C.M. (2001). Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50, 24-31. https://doi.org/10.2337/diabetes.50.1.24
  22. Ritov, V.B., Menshikova, E.V., He, J., Ferrell, R.E., Goodpaster, B.H., and Kelley, D.E. (2005). Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54, 8-14. https://doi.org/10.2337/diabetes.54.1.8
  23. Ryu, H.S., Park, S.Y., Ma, D., Zhang, J., and Lee, W. (2011). The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes. PLoS One 6, e17343. https://doi.org/10.1371/journal.pone.0017343
  24. Simoneau, J.A., and Kelley, D.E. (1997). Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J. Appl. Physiol. 83, 166-171.
  25. Singh, A.B., Guleria, R.S., Nizamutdinova, I.T., Baker, K.M., and Pan, J. (2012). High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling. J. Cell. Physiol. 227, 2632-2644. https://doi.org/10.1002/jcp.23005
  26. Sun, X.J., Goldberg, J.L., Qiao, L.Y., and Mitchell, J.J. (1999). Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. Diabetes 48, 1359-1364. https://doi.org/10.2337/diabetes.48.7.1359
  27. Yuzefovych, L.V., Solodushko, V.A., Wilson, G.L., and Rachek, L.I. (2012). Protection from palmitate-induced mitochondrial DNA damage prevents from mitochondrial oxidative stress, mitochondrial dysfunction, apoptosis, and impaired insulin signaling in rat L6 skeletal muscle cells. Endocrinology 153, 92-100. https://doi.org/10.1210/en.2011-1442

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