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Journal of Gastroenterology

, Volume 52, Issue 8, pp 889–903 | Cite as

Fatty acids in a high-fat diet potentially induce gastric parietal-cell damage and metaplasia in mice

  • Yuki Hirata
  • Takuhito Sezaki
  • Miwa Tamura-Nakano
  • Chinatsu Oyama
  • Teruki Hagiwara
  • Takamasa Ishikawa
  • Shinji Fukuda
  • Kazuhiko Yamada
  • Kazuhide Higuchi
  • Taeko DohiEmail author
  • Yuki I. KawamuraEmail author
Original Article—Alimentary Tract

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.

Keywords

Fatty acid Obesity Single cell analysis Gastric adenocarcinoma 

Abbreviations

DCA

Deoxycholic acid

EM

Electron microscopy

FFA

Free fatty acids

HBSS

Hank’s balanced salt solution

HFD

High fat diet

HK-ATPase

H+/K+-ATPase

LD

Lipid droplet

SPEM

Spasmolytic polypeptide-expressing metaplasia

TFF2

Trefoil factor family 2

RT-PCR

Reverse-transcription PCR

TG

Triacylglycerides

TMRM

Tetramethylrhodamine methyl ester

WHL

White hyperplastic lesion

Notes

Acknowledgements

We thank Prof. N. Mizushima for valuable advises for our experiments. We thank Ms. Y. Nozaki and Ms. M. Inokuchi for their technical assistance. This work was supported partly by grants and contracts from the program Grants-in-Aid for Scientific Research (B), 5H04503 and for TD and Grants-in-Aid for Scientific Research (C), 25460965 for YIK) from the Ministry of Education, Cultures, Sports, Science, and Technology; the Japan Science and Technology Agency; a grant from the National Centre for Global Health and Medicine (22-205, 25-104 for TD, 23-101, 26-110, 26-117, and 27-1406 for YIK), Ministry of Health, Labour, and Welfare; and RIKEN RCAI (TD).

Author contributions

YH, TS, TH, MT-N, CO, TI, SF, TE and YIK, acquisition of data; YIK and TD, study concept and design; YH, TS, TH, KY, KH, SF, TD, and YIK, analysis and interpretation of data; YH, TS, SF, TD, and YIK, drafting of the manuscript; YH, SF, TD and YIK, obtaining funding.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

535_2016_1291_MOESM1_ESM.pdf (5.2 mb)
Supplementary material 1 (PDF 5358 kb)
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Supplementary material 2 (MOV 3391 kb)
535_2016_1291_MOESM3_ESM.mov (2.6 mb)
Supplementary material 3 (MOV 2711 kb)

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Copyright information

© Japanese Society of Gastroenterology 2016

Authors and Affiliations

  1. 1.Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research InstituteNational Center for Global Health and MedicineIchikawaJapan
  2. 2.Communal Laboratory, Research InstituteNational Center for Global Health and MedicineTokyoJapan
  3. 3.Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
  4. 4.Department of SurgeryNational Center for Global Health and MedicineTokyoJapan
  5. 5.2nd Department of Internal MedicineOsaka Medical CollegeTakatsukiJapan

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