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Regulation of Hepatic Gluconeogenesis by Nuclear Receptor Coactivator 6

  • Oh, Gyun-Sik (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Si-Ryong (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Eun-Sook (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoon, Jin (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Shin, Min-Kyung (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Ryu, Hyeon Kyoung (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Dong Seop (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Seung-Whan (Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2021.08.20
  • Accepted : 2022.01.04
  • Published : 2022.04.30

Abstract

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator of nuclear receptors and other transcription factors. A general Ncoa6 knockout mouse was previously shown to be embryonic lethal, but we here generated liver-specific Ncoa6 knockout (Ncoa6 LKO) mice to investigate the metabolic function of NCOA6 in the liver. These Ncoa6 LKO mice exhibited similar blood glucose and insulin levels to wild type but showed improvements in glucose tolerance, insulin sensitivity, and pyruvate tolerance. The decrease in glucose production from pyruvate in these LKO mice was consistent with the abrogation of the fasting-stimulated induction of gluconeogenic genes, phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc). The forskolin-stimulated inductions of Pck1 and G6pc were also dramatically reduced in primary hepatocytes isolated from Ncoa6 LKO mice, whereas the expression levels of other gluconeogenic gene regulators, including cAMP response element binding protein (Creb), forkhead box protein O1 and peroxisome proliferator-activated receptor γ coactivator 1α, were unaltered in the LKO mouse livers. CREB phosphorylation via fasting or forskolin stimulation was normal in the livers and primary hepatocytes of the LKO mice. Notably, it was observed that CREB interacts with NCOA6. The transcriptional activity of CREB was found to be enhanced by NCOA6 in the context of Pck1 and G6pc promoters. NCOA6-dependent augmentation was abolished in cAMP response element (CRE) mutant promoters of the Pck1 and G6pc genes. Our present results suggest that NCOA6 regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.

Keywords

Acknowledgement

We thank the GEAR Core Lab core facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Medical Center for the use of their shared equipment, services and expertise. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (NRF-2018R1A2B6007013, NRF-2021R1H1A2095350); and by a grant (2021IL0038) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

References

  1. Altarejos, J.Y. and Montminy, M. (2011). CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, 141-151. https://doi.org/10.1038/nrm3072
  2. Antonson, P., Schuster, G.U., Wang, L., Rozell, B., Holter, E., Flodby, P., Treuter, E., Holmgren, L., and Gustafsson, J.A. (2003). Inactivation of the nuclear receptor coactivator RAP250 in mice results in placental vascular dysfunction. Mol. Cell. Biol. 23, 1260-1268. https://doi.org/10.1128/MCB.23.4.1260-1268.2003
  3. Basu, R., Chandramouli, V., Dicke, B., Landau, B., and Rizza, R. (2005). Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Diabetes 54, 1942-1948. https://doi.org/10.2337/diabetes.54.7.1942
  4. Benchoula, K., Parhar, I.S., Madhavan, P., and Hwa, W.E. (2021). CREB nuclear transcription activity as a targeting factor in the treatment of diabetes and diabetes complications. Biochem. Pharmacol. 188, 114531. https://doi.org/10.1016/j.bcp.2021.114531
  5. Caira, F., Antonson, P., Pelto-Huikko, M., Treuter, E., and Gustafsson, J.A. (2000). Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J. Biol. Chem. 275, 5308-5317. https://doi.org/10.1074/jbc.275.8.5308
  6. Chevalier, S., Burgess, S.C., Malloy, C.R., Gougeon, R., Marliss, E.B., and Morais, J.A. (2006). The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes 55, 675-681. https://doi.org/10.2337/diabetes.55.03.06.db05-1117
  7. Cline, G.W., Rothman, D.L., Magnusson, I., Katz, L.D., and Shulman, G.I. (1994). 13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. J. Clin. Invest. 94, 2369-2376. https://doi.org/10.1172/JCI117602
  8. Ekberg, K., Landau, B.R., Wajngot, A., Chandramouli, V., Efendic, S., Brunengraber, H., and Wahren, J. (1999). Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. Diabetes 48, 292-298. https://doi.org/10.2337/diabetes.48.2.292
  9. Hanson, R.W. and Patel, Y.M. (1994). Phosphoenolpyruvate carboxykinase (GTP): the gene and the enzyme. Adv. Enzymol. Relat. Areas Mol. Biol. 69, 203-281.
  10. Jitrapakdee, S., Booker, G.W., Cassady, A.I., and Wallace, J.C. (1997). The rat pyruvate carboxylase gene structure. Alternate promoters generate multiple transcripts with the 5'-end heterogeneity. J. Biol. Chem. 272, 20522-20530. https://doi.org/10.1074/jbc.272.33.20522
  11. Jitrapakdee, S., Petchamphai, N., Sunyakumthorn, P., Wallace, J.C., and Boonsaeng, V. (2001). Structural and promoter regions of the murine pyruvate carboxylase gene. Biochem. Biophys. Res. Commun. 287, 411-417. https://doi.org/10.1006/bbrc.2001.5599
  12. Kim, G.H., Lee, K.J., Oh, G.S., Yoon, J., Kim, H.W., and Kim, S.W. (2012). Regulation of hepatic insulin sensitivity by activating signal cointegrator-2. Biochem. J. 447, 437-447. https://doi.org/10.1042/BJ20120861
  13. Kim, G.H., Oh, G.S., Yoon, J., Lee, G.G., Lee, K.U., and Kim, S.W. (2015). Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor. J. Clin. Invest. 125, 183-193. https://doi.org/10.1172/JCI73615
  14. Ko, L., Cardona, G.R., and Chin, W.W. (2000). Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator. Proc. Natl. Acad. Sci. U. S. A. 97, 6212-6217. https://doi.org/10.1073/pnas.97.11.6212
  15. Lee, S.K., Anzick, S.L., Choi, J.E., Bubendorf, L., Guan, X.Y., Jung, Y.K., Kallioniemi, O.P., Kononen, J., Trent, J.M., Azorsa, D., et al. (1999). A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo. J. Biol. Chem. 274, 34283-34293. https://doi.org/10.1074/jbc.274.48.34283
  16. Magnusson, I., Rothman, D.L., Katz, L.D., Shulman, R.G., and Shulman, G.I. (1992). Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 90, 1323-1327. https://doi.org/10.1172/JCI115997
  17. Mahajan, M.A., Das, S., Zhu, H., Tomic-Canic, M., and Samuels, H.H. (2004). The nuclear hormone receptor coactivator NRC is a pleiotropic modulator affecting growth, development, apoptosis, reproduction, and wound repair. Mol. Cell. Biol. 24, 4994-5004. https://doi.org/10.1128/MCB.24.11.4994-5004.2004
  18. Mahajan, M.A. and Samuels, H.H. (2000). A new family of nuclear receptor coregulators that integrate nuclear receptor signaling through CREB-binding protein. Mol. Cell. Biol. 20, 5048-5063. https://doi.org/10.1128/MCB.20.14.5048-5063.2000
  19. Modaressi, S., Brechtel, K., Christ, B., and Jungermann, K. (1998). Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene. Structure, chromosomal localization and tissue-specific expression. Biochem. J. 333 (Pt 2), 359-366.
  20. Nordlie, R.C. and Lardy, H.A. (1963). Mammalian liver phosphoneolpyruvate carboxykinase activities. J. Biol. Chem. 238, 2259-2263. https://doi.org/10.1016/S0021-9258(19)67962-7
  21. Oh, G.S., Lee, G.G., Yoon, J., Oh, W.K., and Kim, S.W. (2015). Selective inhibition of liver X receptor α-mediated lipogenesis in primary hepatocytes by licochalcone A. Chin. Med. 10, 8. https://doi.org/10.3760/cma.j.issn.1673-4777.2015.01.003
  22. Paz, J.C., Park, S., Phillips, N., Matsumura, S., Tsai, W.W., Kasper, L., Brindle, P.K., Zhang, G., Zhou, M.M., Wright, P.E., et al. (2014). Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation. Proc. Natl. Acad. Sci. U. S. A. 111, 17116-17121. https://doi.org/10.1073/pnas.1420389111
  23. Petersen, M.C., Vatner, D.F., and Shulman, G.I. (2017). Regulation of hepatic glucose metabolism in health and disease. Nat. Rev. Endocrinol. 13, 572-587. https://doi.org/10.1038/nrendo.2017.80
  24. Rui, L. (2014). Energy metabolism in the liver. Compr. Physiol. 4, 177-197. https://doi.org/10.1002/cphy.c130024
  25. Samuel, V.T., Liu, Z.X., Qu, X., Elder, B.D., Bilz, S., Befroy, D., Romanelli, A.J., and Shulman, G.I. (2004). Mechanism of hepatic insulin resistance in nonalcoholic fatty liver disease. J. Biol. Chem. 279, 32345-32353. https://doi.org/10.1074/jbc.M313478200
  26. Thiel, G., Al Sarraj, J., and Stefano, L. (2005). cAMP response element binding protein (CREB) activates transcription via two distinct genetic elements of the human glucose-6-phosphatase gene. BMC Mol. Biol. 6, 2. https://doi.org/10.1186/1471-2199-6-2
  27. Thonpho, A., Sereeruk, C., Rojvirat, P., and Jitrapakdee, S. (2010). Identification of the cyclic AMP responsive element (CRE) that mediates transcriptional regulation of the pyruvate carboxylase gene in HepG2 cells. Biochem. Biophys. Res. Commun. 393, 714-719. https://doi.org/10.1016/j.bbrc.2010.02.067
  28. Wajngot, A., Chandramouli, V., Schumann, W.C., Ekberg, K., Jones, P.K., Efendic, S., and Landau, B.R. (2001). Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus. Metabolism 50, 47-52. https://doi.org/10.1053/meta.2001.19422
  29. Wolfe, K.B. and Long, D.T. (2019). Chromatin immunoprecipitation (ChIP) of plasmid-bound proteins in Xenopus egg extracts. Methods Mol. Biol. 1999, 173-184. https://doi.org/10.1007/978-1-4939-9500-4_10
  30. Xing, L. and Quinn, P.G. (1993). Involvement of 3',5'-cyclic adenosine monophosphate regulatory element binding protein (CREB) in both basal and hormone-mediated expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene. Mol. Endocrinol. 7, 1484-1494. https://doi.org/10.1210/mend.7.11.8114762
  31. Yeom, S.Y., Kim, G.H., Kim, C.H., Jung, H.D., Kim, S.Y., Park, J.Y., Pak, Y.K., Rhee, D.K., Kuang, S.Q., Xu, J., et al. (2006). Regulation of insulin secretion and β-cell mass by activating signal cointegrator 2. Mol. Cell. Biol. 26, 4553-4563. https://doi.org/10.1128/MCB.01412-05
  32. Zhang, K., Yin, R., and Yang, X. (2014). O-GlcNAc: a bittersweet switch in liver. Front. Endocrinol. 5, 221. https://doi.org/10.3389/fendo.2014.00221
  33. Zhu, Y., Kan, L., Qi, C., Kanwar, Y.S., Yeldandi, A.V., Rao, M.S., and Reddy, J.K. (2000). Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J. Biol. Chem. 275, 13510-13516. https://doi.org/10.1074/jbc.275.18.13510
  34. Zhu, Y.J., Crawford, S.E., Stellmach, V., Dwivedi, R.S., Rao, M.S., Gonzalez, F.J., Qi, C., and Reddy, J.K. (2003). Coactivator PRIP, the peroxisome proliferator-activated receptor-interacting protein, is a modulator of placental, cardiac, hepatic, and embryonic development. J. Biol. Chem. 278, 1986-1990. https://doi.org/10.1074/jbc.C200634200