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Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal

Author

Listed:
  • Jian-Hui Shi

    (Naval Medical University)

  • Yu-Xia Chen

    (Naval Medical University)

  • Yingying Feng

    (Naval Medical University
    Tianjin Medical University)

  • Xiaohang Yang

    (Tianjin Medical University)

  • Jie Lin

    (Naval Medical University)

  • Ting Wang

    (Tianjin Medical University)

  • Chun-Chun Wei

    (Naval Medical University)

  • Xian-Hua Ma

    (Naval Medical University)

  • Rui Yang

    (Naval Medical University)

  • Dongmei Cao

    (Naval Medical University)

  • Hai Zhang

    (Naval Medical University)

  • Xiangyang Xie

    (Tianjin Medical University)

  • Zhifang Xie

    (Naval Medical University)

  • Weiping J. Zhang

    (Naval Medical University
    Tianjin Medical University)

Abstract

Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

Suggested Citation

  • Jian-Hui Shi & Yu-Xia Chen & Yingying Feng & Xiaohang Yang & Jie Lin & Ting Wang & Chun-Chun Wei & Xian-Hua Ma & Rui Yang & Dongmei Cao & Hai Zhang & Xiangyang Xie & Zhifang Xie & Weiping J. Zhang, 2023. "Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43609-0
    DOI: 10.1038/s41467-023-43609-0
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    References listed on IDEAS

    as
    1. Dongmei Cao & Xianhua Ma & Jiao Cai & Jing Luan & An-Jun Liu & Rui Yang & Yi Cao & Xiaotong Zhu & Hai Zhang & Yu-Xia Chen & Yuguang Shi & Guang-Xia Shi & Dajin Zou & Xuetao Cao & Michael J. Grusby & Z, 2016. "ZBTB20 is required for anterior pituitary development and lactotrope specification," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    2. Leandro R. Soria & Georgios Makris & Alfonso M. D’Alessio & Angela Angelis & Iolanda Boffa & Veronica M. Pravata & Véronique Rüfenacht & Sergio Attanasio & Edoardo Nusco & Paola Arena & Andrew T. Fere, 2022. "O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Gan Liu & Luting Zhou & Hai Zhang & Rong Chen & Ye Zhang & Ling Li & Jun-Yu Lu & Hui Jiang & Dong Liu & Shasha Qi & Ying-Ming Jiang & Kai Yin & Zhifang Xie & Yuguang Shi & Yong Liu & Xuetao Cao & Yu-X, 2017. "Regulation of hepatic lipogenesis by the zinc finger protein Zbtb20," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
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