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Original article
CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity
  1. Naoto Fujiwara1,
  2. Hayato Nakagawa1,
  3. Kenichiro Enooku1,
  4. Yotaro Kudo1,
  5. Yuki Hayata1,
  6. Takuma Nakatsuka1,
  7. Yasuo Tanaka1,
  8. Ryosuke Tateishi1,
  9. Yohko Hikiba2,
  10. Kento Misumi3,
  11. Mariko Tanaka3,
  12. Akimasa Hayashi3,
  13. Junji Shibahara3,
  14. Masashi Fukayama3,
  15. Junichi Arita4,
  16. Kiyoshi Hasegawa4,
  17. Hadassa Hirschfield5,
  18. Yujin Hoshida5,
  19. Yoshihiro Hirata1,
  20. Motoyuki Otsuka1,
  21. Keisuke Tateishi1,
  22. Kazuhiko Koike1
  1. 1 Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
  2. 2 Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
  3. 3 Department of Pathology, The University of Tokyo, Tokyo, Japan
  4. 4 Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
  5. 5 Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
  1. Correspondence to Dr Hayato Nakagawa, Department of Gastroenterology, The University of Tokyo, Tokyo 113-8655, Japan; hanakagawa-tky{at}umin.ac.jp

Abstract

Objective Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration.

Design Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated.

Results The extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid β-oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src-mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo.

Conclusion In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.

  • hepatocellular carcinoma
  • metabolome
  • acylcarnitine
  • CPT2
  • metabolic reprograming

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Footnotes

  • NF and HN contributed equally.

  • Contributors NF obtained the funding, performed in vitro and in vivo experiments, statistical analyses and drafted and revised the manuscript. HN obtained the funding, performed in vitro and in vivo experiments, statistical analyses and drafted and revised the manuscript. KE, RT, JA and KH recruited patients and collected data. KM, MT, AH, JS and MF reviewed histological slides. YH, HH and YH provided valuable technical support for experiments. YK, YH, TN, YT, YH, MO and KT critically revised the manuscript for important intellectual content. KK obtained the funding, conceived and supervised the study, drafted and revised the manuscript. All authors were involved in the critical revision of the manuscript for important intellectual content.

  • Funding This study was supported by Uehara Memorial Foundation (NF and HN), JSPS KAKENHI Grant Number 15K19313, Viral Hepatitis Research Foundation of Japan, Daiichi Sankyo Foundation of Life Science, Bristol-Myers Squibb Research Grant (HN), Program for Basic and Clinical Research on Hepatitis from Japan Agency for Medical Research and Development, AMED under Grant Number JP17fk0210304 (HN and KK) and AMED-CREST under Grant Number JP17gm0710004 (HN).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the Ethics Committee for Animal Experimentation of the University of Tokyo and the Institute for Adult Diseases, Asahi Life Foundation.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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