IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42424-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42424-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42424-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Alberto Díez-Sánchez & Håvard T. Lindholm & Pia M. Vornewald & Jenny Ostrop & Rouan Yao & Andrew B. Single & Anne Marstad & Naveen Parmar & Tovah N. Shaw & Mara Martín-Alonso & Menno J. Oudhoff, 2024. "LSD1 drives intestinal epithelial maturation and controls small intestinal immune cell composition independent of microbiota in a murine model," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Susanne Kessler & Bradly Burke & Geoffroy Andrieux & Jan Schinköthe & Lea Hamberger & Johannes Kacza & Shijun Zhan & Clara Reasoner & Taru S. Dutt & Maria Kaukab Osman & Marcela Henao-Tamayo & Julian , 2024. "Deciphering bat influenza H18N11 infection dynamics in male Jamaican fruit bats on a single-cell level," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Xiwen Xiong & Chenyan Yang & Wei-Qi He & Jiahui Yu & Yue Xin & Xinge Zhang & Rong Huang & Honghui Ma & Shaofang Xu & Zun Li & Jie Ma & Lin Xu & Qunyi Wang & Kaiqun Ren & Xiaoli S. Wu & Christopher R. , 2022. "Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Sandor Spisak & David Chen & Pornlada Likasitwatanakul & Paul Doan & Zhixin Li & Pratyusha Bala & Laura Vizkeleti & Viktoria Tisza & Pushpamali Silva & Marios Giannakis & Brian Wolpin & Jun Qi & Nilay, 2024. "Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Lucia Taraborrelli & Yasin Şenbabaoğlu & Lifen Wang & Junghyun Lim & Kerrigan Blake & Noelyn Kljavin & Sarah Gierke & Alexis Scherl & James Ziai & Erin McNamara & Mark Owyong & Shilpa Rao & Aslihan Ka, 2023. "Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Tianwei Yu, 2018. "A new dynamic correlation algorithm reveals novel functional aspects in single cell and bulk RNA-seq data," PLOS Computational Biology, Public Library of Science, vol. 14(8), pages 1-22, August.
    8. Greg Holmes & Ana S. Gonzalez-Reiche & Madrikha Saturne & Susan M. Motch Perrine & Xianxiao Zhou & Ana C. Borges & Bhavana Shewale & Joan T. Richtsmeier & Bin Zhang & Harm Bakel & Ethylin Wang Jabs, 2021. "Single-cell analysis identifies a key role for Hhip in murine coronal suture development," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    9. Jia Li & Alan J. Simmons & Caroline V. Hawkins & Sophie Chiron & Marisol A. Ramirez-Solano & Naila Tasneem & Harsimran Kaur & Yanwen Xu & Frank Revetta & Paige N. Vega & Shunxing Bao & Can Cui & Regin, 2024. "Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    10. Adam E. Hall & Sebastian Öther-Gee Pohl & Patrizia Cammareri & Stuart Aitken & Nicholas T. Younger & Michela Raponi & Caroline V. Billard & Alfonso Bolado Carrancio & Aslihan Bastem & Paz Freile & Fio, 2022. "RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Jorge Mata-Garrido & Yao Xiang & Yunhua Chang-Marchand & Caroline Reisacher & Elisabeth Ageron & Ida Chiara Guerrera & Iñigo Casafont & Aurelia Bruneau & Claire Cherbuy & Xavier Treton & Anne Dumay & , 2022. "The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    12. Kathleen Shah & Muralidhara Rao Maradana & M. Joaquina Delàs & Amina Metidji & Frederike Graelmann & Miriam Llorian & Probir Chakravarty & Ying Li & Mauro Tolaini & Michael Shapiro & Gavin Kelly & Chr, 2022. "Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Lucy Xia & Christy Lee & Jingyi Jessica Li, 2024. "Statistical method scDEED for detecting dubious 2D single-cell embeddings and optimizing t-SNE and UMAP hyperparameters," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    14. María A. Duque-Correa & David Goulding & Faye H. Rodgers & J. Andrew Gillis & Claire Cormie & Kate A. Rawlinson & Allison J. Bancroft & Hayley M. Bennett & Magda E. Lotkowska & Adam J. Reid & Annelies, 2022. "Defining the early stages of intestinal colonisation by whipworms," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Md Tauhidul Islam & Jen-Yeu Wang & Hongyi Ren & Xiaomeng Li & Masoud Badiei Khuzani & Shengtian Sang & Lequan Yu & Liyue Shen & Wei Zhao & Lei Xing, 2022. "Leveraging data-driven self-consistency for high-fidelity gene expression recovery," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Ihab Ansari & Llorenç Solé-Boldo & Meshi Ridnik & Julian Gutekunst & Oliver Gilliam & Maria Korshko & Timur Liwinski & Birgit Jickeli & Noa Weinberg-Corem & Michal Shoshkes-Carmel & Eli Pikarsky & Era, 2023. "TET2 and TET3 loss disrupts small intestine differentiation and homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Ruiqing Wang & Xinyu Yang & Jinting Liu & Fang Zhong & Chen Zhang & Yuhong Chen & Tao Sun & Chunyan Ji & Daoxin Ma, 2022. "Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    18. Jiarui Ding & John J. Garber & Amiko Uchida & Ariel Lefkovith & Grace T. Carter & Praveen Vimalathas & Lauren Canha & Michael Dougan & Kyle Staller & Joseph Yarze & Toni M. Delorey & Orit Rozenblatt-R, 2024. "An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. M. Büttner & J. Ostner & C. L. Müller & F. J. Theis & B. Schubert, 2021. "scCODA is a Bayesian model for compositional single-cell data analysis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    20. Yue Wang & Yanbo Yu & Lixiang Li & Mengqi Zheng & Jiawei Zhou & Haifan Gong & Bingcheng Feng & Xiao Wang & Xuanlin Meng & Yanyan Cui & Yanan Xia & Shuzheng Chu & Lin Lin & Huijun Chang & Ruchen Zhou &, 2023. "Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42424-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.