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



Obesity is associated with risk of adenocarcinoma in the proximal stomach. We aimed to identify the links between dietary fat and gastric premalignant lesions.


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.


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.


Dietary lipids induce parietal-cell damage and may lead to the development of precancerous metaplasia.


Fatty acid Obesity Single cell analysis Gastric adenocarcinoma 



Deoxycholic acid


Electron microscopy


Free fatty acids


Hank’s balanced salt solution


High fat diet




Lipid droplet


Spasmolytic polypeptide-expressing metaplasia


Trefoil factor family 2


Reverse-transcription PCR




Tetramethylrhodamine methyl ester


White hyperplastic lesion



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) (3.3 mb)
Supplementary material 2 (MOV 3391 kb) (2.6 mb)
Supplementary material 3 (MOV 2711 kb)


  1. 1.
    Ogden CL, Yanovski SZ, Carroll MD, et al. The epidemiology of obesity. Gastroenterology. 2007;132(6):2087–102.CrossRefPubMedGoogle Scholar
  2. 2.
    Aleman JO, Eusebi LH, Ricciardiello L, et al. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology. 2014;146(2):357–73.CrossRefPubMedGoogle Scholar
  3. 3.
    Chow WH, Blot WJ, Vaughan TL, et al. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst. 1998;90(2):150–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Merry AH, Schouten LJ, Goldbohm RA, et al. Body mass index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study. Gut. 2007;56(11):1503–11.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Olefson S, Moss SF. Obesity and related risk factors in gastric cardia adenocarcinoma. Gastric Cancer. 2015;18(1):23–32.CrossRefPubMedGoogle Scholar
  6. 6.
    Steffen A, Huerta JM, Weiderpass E, et al. General and abdominal obesity and risk of esophageal and gastric adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2015;37:646–57.CrossRefGoogle Scholar
  7. 7.
    Abnet CC, Freedman ND, Hollenbeck AR, et al. A prospective study of BMI and risk of oesophageal and gastric adenocarcinoma. Eur J Cancer. 2008;44(3):465–71.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature. 2014;514(7523):508–12.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Turnbaugh PJ, Backhed F, Fulton L, et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213–23.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101.CrossRefPubMedGoogle Scholar
  11. 11.
    Chak A, Falk G, Grady WM, et al. Assessment of familiality, obesity, and other risk factors for early age of cancer diagnosis in adenocarcinomas of the esophagus and gastroesophageal junction. Am J Gastroenterol. 2009;104(8):1913–21.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    de Jonge PJ, van Blankenstein M, Grady WM, et al. Barrett’s oesophagus: epidemiology, cancer risk and implications for management. Gut. 2014;63(1):191–202.CrossRefPubMedGoogle Scholar
  13. 13.
    Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Quante M, Abrams JA, Lee Y, et al. Barrett esophagus: what a mouse model can teach us about human disease. Cell Cycle. 2012;11(23):4328–38.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Tatematsu M, Tsukamoto T, Inada K. Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer Sci. 2003;94(2):135–41.CrossRefPubMedGoogle Scholar
  16. 16.
    Goldenring JR, Nam KT. Oxyntic atrophy, metaplasia, and gastric cancer. Prog Mol Biol Transl Sci. 2010;96:117–31.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Goldenring JR, Nomura S. Differentiation of the gastric mucosa III. Animal models of oxyntic atrophy and metaplasia. Am J Physiol Gastrointest Liver Physiol. 2006;291(6):999–1004.CrossRefGoogle Scholar
  18. 18.
    Nomura S, Baxter T, Yamaguchi H, et al. Spasmolytic polypeptide expressing metaplasia to preneoplasia in H. felis-infected mice. Gastroenterology. 2004;127(2):582–94.CrossRefPubMedGoogle Scholar
  19. 19.
    Nomura S, Yamaguchi H, Ogawa M, et al. Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2005;288(2):G362–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Oshima M, Oshima H, Matsunaga A, et al. Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice. Cancer Res. 2005;65(20):9147–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Schmidt PH, Lee JR, Joshi V, et al. Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma. Lab Invest. 1999;79(6):639–46.PubMedGoogle Scholar
  22. 22.
    Wang TC, Goldenring JR, Dangler C, et al. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology. 1998;114(4):675–89.CrossRefPubMedGoogle Scholar
  23. 23.
    Schumacher MA, Feng R, Aihara E, et al. Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NFkappaB pathway activation: the use of a novel in vitro model to study epithelial response to infection. Helicobacter. 2015;20(1):19–28.CrossRefPubMedGoogle Scholar
  24. 24.
    Fujimoto T, Ohsaki Y, Suzuki M, et al. Imaging lipid droplets by electron microscopy. Methods Cell Biol. 2013;116:227–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Quante M, Bhagat G, Abrams JA, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell. 2012;21(1):36–51.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Backhed F, Manchester JK, Semenkovich CF, et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA. 2007;104(3):979–84.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126–32.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hagio M, Matsumoto M, Fukushima M, et al. Improved analysis of bile acids in tissues and intestinal contents of rats using LC/ESI-MS. J Lipid Res. 2009;50(1):173–80.CrossRefPubMedGoogle Scholar
  29. 29.
    Ikeda K, Oike Y, Shimizu T, et al. Global analysis of triacylglycerols including oxidized molecular species by reverse-phase high resolution LC/ESI-QTOF MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(25):2639–47.CrossRefPubMedGoogle Scholar
  30. 30.
    Glinghammar B, Inoue H, Rafter JJ. Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1. Carcinogenesis. 2002;23(5):839–45.CrossRefPubMedGoogle Scholar
  31. 31.
    Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Progress Lipid Res. 2003;42(4):318–43.CrossRefGoogle Scholar
  32. 32.
    Bailey AP, Koster G, Guillermier C, et al. Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila. Cell. 2015;163(2):340–53.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Naito Y, Uchiyama K, Kuroda M, et al. Role of pancreatic trypsin in chronic esophagitis induced by gastroduodenal reflux in rats. J Gastroenterol. 2006;41(3):198–208.CrossRefPubMedGoogle Scholar
  34. 34.
    Farese RV Jr, Walther TC. Lipid droplets finally get a little R-E-S-P-E-C-T. Cell. 2009;139(5):855–60.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res. 2008;1(5):329–38.CrossRefGoogle Scholar
  36. 36.
    Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst. 2006;98(20):1445–52.CrossRefPubMedGoogle Scholar

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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