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Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner

Authors

  • Dahee Choi,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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    • *These authors contributed equally to this work.

  • Kyoung-Jin Oh,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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    • *These authors contributed equally to this work.

  • Hye-Sook Han,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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  • Young-Sil Yoon,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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  • Chang-Yun Jung,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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  • Seong-Tae Kim,

    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
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  • Seung-Hoi Koo

    Corresponding author
    1. Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
    • Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon 440-746, Gyeonggi-do, Korea
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    • fax: +82-31-299-6239


  • Potential conflict of interest: Nothing to report.

Abstract

Postprandial insulin plays a critical role in suppressing hepatic glucose production to maintain euglycemia in mammals. Insulin-dependent activation of protein kinase B (Akt) regulates this process, in part, by inhibiting FoxO1-dependent hepatic gluconeogenesis by direct phosphorylation and subsequent cytoplasmic exclusion. Previously, it was demonstrated that protein arginine methyltransferase 1 (PRMT1)-dependent arginine modification of FoxO1 interferes with Akt-dependent phosphorylation, both in cancer cells and in the Caenorhabditis elegans model, suggesting that this additional modification of FoxO1 might be critical in its transcriptional activity. In this study, we attempted to directly test the effect of arginine methylation of FoxO1 on hepatic glucose metabolism. The ectopic expression of PRMT1 enhanced messenger RNA levels of FoxO1 target genes in gluconeogenesis, resulting in increased glucose production from primary hepatocytes. Phosphorylation of FoxO1 at serine 253 was reduced with PRMT1 expression, without affecting the serine 473 phosphorylation of Akt. Conversely, knockdown of PRMT1 promoted an inhibition of FoxO1 activity and hepatic gluconeogenesis by enhancing the phosphorylation of FoxO1. In addition, genetic haploinsufficiency of Prmt1 reduced hepatic gluconeogenesis and blood-glucose levels in mouse models, underscoring the importance of this factor in hepatic glucose metabolism in vivo. Finally, we were able to observe an amelioration of the hyperglycemic phenotype of db/db mice with PRMT1 knockdown, showing a potential importance of this protein as a therapeutic target for the treatment of diabetes. Conclusion: Our data strongly suggest that the PRMT1-dependent regulation of FoxO1 is critical in hepatic glucose metabolism in vivo. (HEPATOLOGY 2012)

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