Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis

• Published in: Nature communications Vol. 14; no. 1; p. 6763
• Main Authors: Tamura, Ryutaro, Sabu, Yusuke, Mizuno, Tadahaya, Mizuno, Seiya, Nakano, Satoshi, Suzuki, Mitsuyoshi, Abukawa, Daiki, Kaji, Shunsaku, Azuma, Yoshihiro, Inui, Ayano, Okamoto, Tatsuya, Shimizu, Seiichi, Fukuda, Akinari, Sakamoto, Seisuke, Kasahara, Mureo, Takahashi, Satoru, Kusuhara, Hiroyuki, Zen, Yoh, Ando, Tomohiro, Hayashi, Hisamitsu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/63; 64/60; 692/308/575; 692/4020/4021/1607/2751; 692/699/1503/1607/2751; 692/699/1702/295; Absorption; Age; Choline; Epithelial cells; Epithelium; Gallbladder diseases; Gastroenterology; Hepatology; Hospitals; Humanities and Social Sciences; Infant mortality; Intestine; Lecithin; Lipids; Liver; Malabsorption; Metabolites; Metabolomics; multidisciplinary; Mutation; Nutrient deficiency; Pediatrics; Phosphatidylcholine; Phospholipids; Proteins; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42424-x

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 (Atp8b1 IEC-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 Atp8b1 IEC-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. Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.