CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis

Abstract

During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis1. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia2. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) in concert with various other transcriptional regulators3,4,5,6,7,8. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid– and aspartic acid–rich COOH-terminal domain 2) interacts with many of these molecules9,10,11, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1α. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP–protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1α by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5–like 2 (GCN5). The consequent downregulation of PGC-1α acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)–thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1α activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1α acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia.

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Figure 1: CITED2 is upregulated by fasting and glucagon-cAMP and promotes gluconeogenic gene expression.
Figure 2: CITED2 increases hepatic glucose production in vivo through the upregulation of gluconeogenic gene expression in the liver.
Figure 3: CITED2 enhances PGC-1α coactivation activity in primary hepatocytes.
Figure 4: CITED2 inhibits GCN5-dependent PGC-1α acetylation by interfering with the PGC-1α–GCN5 interaction in an insulin-sensitive manner.

References

  1. 1

    Cahill, G.F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).

  2. 2

    Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).

  3. 3

    Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003).

  4. 4

    Matsumoto, M., Pocai, A., Rossetti, L., Depinho, R.A. & Accili, D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 6, 208–216 (2007).

  5. 5

    Rhee, J. et al. Regulation of hepatic fasting response by PPARγ coactivator-1α (PGC-1): requirement for hepatocyte nuclear factor 4α in gluconeogenesis. Proc. Natl. Acad. Sci. USA 100, 4012–4017 (2003).

  6. 6

    Yoon, J.C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

  7. 7

    Puigserver, P. et al. Activation of PPARγ coactivator-1 through transcription factor docking. Science 286, 1368–1371 (1999).

  8. 8

    Matsumoto, M. & Accili, D. The tangled path to glucose production. Nat. Med. 12, 33–34 (2006).

  9. 9

    Qu, X. et al. Cited2, a coactivator of HNF4α, is essential for liver development. EMBO J. 26, 4445–4456 (2007).

  10. 10

    Tien, E.S., Davis, J.W. & Vanden Heuvel, J.P. Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor α coregulator. J. Biol. Chem. 279, 24053–24063 (2004).

  11. 11

    Bhattacharya, S. et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13, 64–75 (1999).

  12. 12

    Bamforth, S.D. et al. Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat. Genet. 29, 469–474 (2001).

  13. 13

    Yin, Z. et al. The essential role of Cited2, a negative regulator for HIF-1α, in heart development and neurulation. Proc. Natl. Acad. Sci. USA 99, 10488–10493 (2002).

  14. 14

    Chen, Y., Haviernik, P., Bunting, K.D. & Yang, Y.C. Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood 110, 2889–2898 (2007).

  15. 15

    Kranc, K.R. et al. Cited2 is an essential regulator of adult hematopoietic stem cells. Cell Stem Cell 5, 659–665 (2009).

  16. 16

    Zhou, X.Y. et al. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat. Med. 10, 633–637 (2004).

  17. 17

    Herzig, S. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001).

  18. 18

    Koo, S.H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

  19. 19

    Lin, J., Handschin, C. & Spiegelman, B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

  20. 20

    Rodgers, J.T., Lerin, C., Gerhart-Hines, Z. & Puigserver, P. Metabolic adaptations through the PGC-1α and SIRT1 pathways. FEBS Lett. 582, 46–53 (2008).

  21. 21

    Rodgers, J.T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

  22. 22

    Nemoto, S., Fergusson, M.M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005).

  23. 23

    Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α. Cell Metab. 3, 429–438 (2006).

  24. 24

    Li, X., Monks, B., Ge, Q. & Birnbaum, M.J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012–1016 (2007).

  25. 25

    Rodgers, J.T., Haas, W., Gygi, S.P. & Puigserver, P. Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis. Cell Metab. 11, 23–34 (2010).

  26. 26

    Jeninga, E.H., Schoonjans, K. & Auwerx, J. Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29, 4617–4624 (2010).

  27. 27

    Dominy, J.E. Jr., Lee, Y., Gerhart-Hines, Z. & Puigserver, P. Nutrient-dependent regulation of PGC-1α's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim. Biophys. Acta 1804, 1676–1683 (2010).

  28. 28

    Matsumoto, M., Han, S., Kitamura, T. & Accili, D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J. Clin. Invest. 116, 2464–2472 (2006).

  29. 29

    Miyake, K. et al. Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J. Clin. Invest. 110, 1483–1491 (2002).

  30. 30

    Schmoll, D., Grempler, R., Barthel, A., Joost, H.G. & Walther, R. Phorbol ester-induced activation of mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase and extracellular-signal-regulated protein kinase decreases glucose-6-phosphatase gene expression. Biochem. J. 357, 867–873 (2001).

  31. 31

    Matsumoto, M. et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes 51, 1672–1680 (2002).

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Acknowledgements

We thank D. Schmoll (Sanofi-Aventis Deutschland GmbH) for the G6PC-promoter reporter plasmid, H. Shimano (University of Tsukuba) for the pcDNA3.1-3 × Flag-HNF-4α plasmid and H. Takamoto for technical assistance. This work was supported by a Grant-in-Aid for Creative Scientific Research (to M.K.) and a Grant-in-Aid for Scientific Research (C) (21591155 to M.M.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant from the National Center for Global Health and Medicine (21S116 to M.M.), a grant from Takeda Science Foundation (to M.M.) and a Novo Nordisk Pharma Insulin Award (to M.M.).

Author information

M.M., T.N. and M.K. conceived of the experiments, and M.S., M.M. and M.K. designed the experiments. M.S., M.M., T.T., C.Y., K.I., H.I., T.H., K.T., Y.K., K.Y., R.H. and Y.M. performed the experiments. M.S., M.M. and M.K. interpreted the data and wrote the manuscript. M.M. and M.K. supervised the study.

Correspondence to Michihiro Matsumoto or Masato Kasuga.

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The authors declare no competing financial interests.

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Sakai, M., Matsumoto, M., Tujimura, T. et al. CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis. Nat Med 18, 612–617 (2012). https://doi.org/10.1038/nm.2691

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