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

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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.

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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

References

  1. Ogden CL, Yanovski SZ, Carroll MD, et al. The epidemiology of obesity. Gastroenterology. 2007;132(6):2087–102.

    Article  PubMed  Google Scholar 

  2. Aleman JO, Eusebi LH, Ricciardiello L, et al. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology. 2014;146(2):357–73.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Olefson S, Moss SF. Obesity and related risk factors in gastric cardia adenocarcinoma. Gastric Cancer. 2015;18(1):23–32.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Goldenring JR, Nam KT. Oxyntic atrophy, metaplasia, and gastric cancer. Prog Mol Biol Transl Sci. 2010;96:117–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  24. Fujimoto T, Ohsaki Y, Suzuki M, et al. Imaging lipid droplets by electron microscopy. Methods Cell Biol. 2013;116:227–51.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  31. Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Progress Lipid Res. 2003;42(4):318–43.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res. 2008;1(5):329–38.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. 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

    Yuki Hirata, Takuhito Sezaki, Teruki Hagiwara, Taeko Dohi & Yuki I. Kawamura

  2. Communal Laboratory, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan

    Miwa Tamura-Nakano & Chinatsu Oyama

  3. Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan

    Takamasa Ishikawa & Shinji Fukuda

  4. Department of Surgery, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan

    Kazuhiko Yamada

  5. 2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan

    Yuki Hirata & Kazuhide Higuchi

Authors
  1. Yuki Hirata
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  2. Takuhito Sezaki
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Corresponding authors

Correspondence to Taeko Dohi or Yuki I. Kawamura.

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The authors declare that they have no conflict of interest.

Additional information

Accession # for transcriptome data: GSE87594.

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Below is the link to the electronic supplementary material. More Materials and Methods are described in the Electronic Supplementary Material and Supplementary Table 2.

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Hirata, Y., Sezaki, T., Tamura-Nakano, M. et al. Fatty acids in a high-fat diet potentially induce gastric parietal-cell damage and metaplasia in mice. J Gastroenterol 52, 889–903 (2017). https://doi.org/10.1007/s00535-016-1291-0

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  • DOI: https://doi.org/10.1007/s00535-016-1291-0

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