Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis

Ryutaro Tamura, Yusuke Sabu, Tadahaya Mizuno, Seiya Mizuno, Satoshi Nakano, Mitsuyoshi Suzuki, Daiki Abukawa, Shunsaku Kaji, Yoshihiro Azuma, Ayano Inui, Tatsuya Okamoto, Seiichi Shimizu, Akinari Fukuda, Seisuke Sakamoto, Mureo Kasahara, Satoru Takahashi, Hiroyuki Kusuhara, Yoh Zen, Tomohiro Ando and Hisamitsu Hayashi ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42424-x

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