CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity

Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki OtsukaKeisuke Tateishi, Kazuhiko Koike

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1493-1503
Number of pages11
JournalGut
Volume67
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

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    Fujiwara, N., Nakagawa, H., Enooku, K., Kudo, Y., Hayata, Y., Nakatsuka, T., Tanaka, Y., Tateishi, R., Hikiba, Y., Misumi, K., Tanaka, M., Hayashi, A., Shibahara, J., Fukayama, M., Arita, J., Hasegawa, K., Hirschfield, H., Hoshida, Y., Hirata, Y., ... Koike, K. (2018). CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut, 67(8), 1493-1503. https://doi.org/10.1136/gutjnl-2017-315193