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Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis

Author

Listed:
  • Ryutaro Tamura

    (The University of Tokyo)

  • Yusuke Sabu

    (The University of Tokyo)

  • Tadahaya Mizuno

    (The University of Tokyo)

  • Seiya Mizuno

    (University of Tsukuba)

  • Satoshi Nakano

    (Juntendo University Graduate School of Medicine)

  • Mitsuyoshi Suzuki

    (Juntendo University Graduate School of Medicine)

  • Daiki Abukawa

    (Miyagi Children’s Hospital)

  • Shunsaku Kaji

    (Tsuyama-Chuo Hospital)

  • Yoshihiro Azuma

    (Yamaguchi University Graduate School of Medicine)

  • Ayano Inui

    (Saiseikai Yokohama City Eastern Hospital)

  • Tatsuya Okamoto

    (Kyoto University Hospital)

  • Seiichi Shimizu

    (National Center for Child Health and Development)

  • Akinari Fukuda

    (National Center for Child Health and Development)

  • Seisuke Sakamoto

    (National Center for Child Health and Development)

  • Mureo Kasahara

    (National Center for Child Health and Development)

  • Satoru Takahashi

    (University of Tsukuba)

  • Hiroyuki Kusuhara

    (The University of Tokyo)

  • Yoh Zen

    (King’s College Hospital & King’s College London)

  • Tomohiro Ando

    (Axcelead Drug Discovery Partners, Inc.)

  • Hisamitsu Hayashi

    (The University of Tokyo)

Abstract

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.

Suggested Citation

  • Ryutaro Tamura & Yusuke Sabu & Tadahaya Mizuno & Seiya Mizuno & Satoshi Nakano & Mitsuyoshi Suzuki & Daiki Abukawa & Shunsaku Kaji & Yoshihiro Azuma & Ayano Inui & Tatsuya Okamoto & Seiichi Shimizu & , 2023. "Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42424-x
    DOI: 10.1038/s41467-023-42424-x
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    References listed on IDEAS

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    1. Adam L. Haber & Moshe Biton & Noga Rogel & Rebecca H. Herbst & Karthik Shekhar & Christopher Smillie & Grace Burgin & Toni M. Delorey & Michael R. Howitt & Yarden Katz & Itay Tirosh & Semir Beyaz & Da, 2017. "A single-cell survey of the small intestinal epithelium," Nature, Nature, vol. 551(7680), pages 333-339, November.
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