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

Nature Medicine volume 18, pages 612–617 (2012)Cite this article

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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.

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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.).

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Authors and Affiliations

  1. Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Mashito Sakai, Michihiro Matsumoto, Tomoko Tujimura, Cao Yongheng & Kenjiro Inagaki

  2. Department of Internal Medicine, Division of Diabetes, Metabolism and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan

    Mashito Sakai, Tetsuya Noguchi, Tetsuya Hosooka, Kazuo Takazawa & Yoshiaki Kido

  3. Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan

    Hiroshi Inoue

  4. Department of Biophysics, Division of Medical Chemistry, Kobe University Graduate School of Health Sciences, Kobe, Hyogo, Japan

    Yoshiaki Kido

  5. Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Kazuki Yasuda

  6. Pharmacology Research Laboratories, Dainippon Sumitomo Pharmaceuticals, Suita, Osaka, Japan

    Ryuji Hiramatsu & Yasushi Matsuki

  7. Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Masato Kasuga

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  1. Mashito Sakai
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Contributions

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.

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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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