title: Fatty acids in a high-fat diet potentially induce gastric parietal-cell damage and metaplasia in mice.
abstract: BACKGROUND
  Obesity is associated with risk of adenocarcinoma in the proximal stomach. We aimed to identify the links between dietary fat and gastric premalignant lesions.
  
  
  METHODS
  C57BL/6 mice were fed high fat diet (HFD), and gastric mucosa was histologically analysed. Morphological changes were also analysed using an electron microscope. Transcriptome analysis of purified parietal cells was performed, and non-parietal gastric corpus epithelial cells were subjected to single-cell gene-expression profiling. Composition of gastric contents of HFD-fed mice was compared with that of the HFD itself. Lipotoxicity of free fatty acids (FFA) was examined in primary culture and organoid culture of mouse gastric epithelial cells in vitro, as well as in vivo, feeding FFA-rich diets.
  
  
  RESULTS
  During ~8-20 weeks of HFD feeding, the parietal cells of the stomach displayed mitochondrial damage, and a total of 23% of the mice developed macroscopically distinct metaplastic lesions in the gastric corpus mucosa. Transcriptome analysis of parietal cells indicated that feeding HFD enhanced pathways related to cell death. Histological analysis and gene-expression profiling indicated that the lesions were similar to previously reported precancerous lesions identified as spasmolytic polypeptide-expressing metaplasia. FFAs, including linoleic acid with refluxed bile acids were detected in the stomachs of the HFD-fed mice. In vitro, FFAs impaired mitochondrial function and decreased the viability of parietal cells. In vivo, linoleic acid-rich diet, but not stearic acid-rich diet induced parietal-cell loss and metaplastic changes in mice.
  
  
  CONCLUSIONS
  Dietary lipids induce parietal-cell damage and may lead to the development of precancerous metaplasia.
authors.affiliation: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.|2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
authors.forename: Takuhito
authors.initials: T
authors.lastname: Sezaki
authors.affiliation: Communal Laboratory, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tamura-Nakano
authors.affiliation: Communal Laboratory, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Oyama
authors.affiliation: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Hagiwara
authors.affiliation: Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Surgery, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.affiliation: 2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan. dohi@ri.ncgm.go.jp.
authors.forename: Taeko
authors.identifier: http://orcid.org/0000-0002-3411-1097
authors.initials: T
authors.lastname: Dohi
authors.affiliation: Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan. kawamura@ri.ncgm.go.jp.
authors.forename: Yuki I
authors.initials: YI
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004847:Epithelial Cells / Q000473:pathology; D005227:Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005750:Gastric Juice / Q000378:metabolism; D005753:Gastric Mucosa / Q000473:pathology*; D020869:Gene Expression Profiling; D019787:Linoleic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D008679:Metaplasia / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D061251:Primary Cell Culture; D013229:Stearic Acids / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D013229:Stearic Acids; D019787:Linoleic Acid
keywords: Fatty acid; Gastric adenocarcinoma; Obesity; Single cell analysis