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Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer

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Abstract

Background

Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer.

Methods

We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo.

Results

In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index.

Conclusions

We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer.

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Data Availability

The datasets generated/analyzed during the current study are not publicly available because they contain private information pertaining to the research participants but are available on request from the corresponding author.

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This study was partially funded by Research for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (JP17im0210606 and JP20im0210111) for Tetsuji Naka.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita Suita, Japan

    Kota Kawabata, Tsuyoshi Takahashi, Koji Tanaka, Yukinori Kurokawa, Kazuyoshi Yamamoto, Takuro Saito, Kota Momose, Kotaro Yamashita, Tomoki Makino, Takashi Yokouchi, Kunihiko Kawai, Kiyokazu Nakajima, Hidetoshi Eguchi & Yuichiro Doki

  2. Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University School of Medicine, Yahaba, Japan

    Satoshi Serada & Tetsuji Naka

  3. Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan

    Minoru Fujimoto & Tetsuji Naka

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  1. Kota Kawabata
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Contributions

Kota Kawabata wrote the initial draft of the manuscript. Tsuyoshi Takahashi contributed to the analysis and interpretation of data and assisted in the preparation of the manuscript. All coauthors contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to accuracy or integrity of any part of the work are appropriately investigated and resolved. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

Corresponding author

Correspondence to Tsuyoshi Takahashi.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. The Human Ethics Review Committee of Osaka University Graduate School of Medicine approved the protocol for this retrospective study and each participant provided written informed consent for study participation (ethical approval number: No. 23247).

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed. The Osaka University Animal Experiments Committee had given approval for the animal studies (ethical approval number: 04–108-000).

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Consent for publication was obtained from the person whose data were on the paper.

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Kawabata, K., Takahashi, T., Tanaka, K. et al. Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer. Gastric Cancer 27, 1258–1272 (2024). https://doi.org/10.1007/s10120-024-01552-z

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  • DOI: https://doi.org/10.1007/s10120-024-01552-z

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