RT Journal Article
SR Electronic
T1 CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2017-315193
DO 10.1136/gutjnl-2017-315193
A1 Naoto Fujiwara
A1 Hayato Nakagawa
A1 Kenichiro Enooku
A1 Yotaro Kudo
A1 Yuki Hayata
A1 Takuma Nakatsuka
A1 Yasuo Tanaka
A1 Ryosuke Tateishi
A1 Yohko Hikiba
A1 Kento Misumi
A1 Mariko Tanaka
A1 Akimasa Hayashi
A1 Junji Shibahara
A1 Masashi Fukayama
A1 Junichi Arita
A1 Kiyoshi Hasegawa
A1 Hadassa Hirschfield
A1 Yujin Hoshida
A1 Yoshihiro Hirata
A1 Motoyuki Otsuka
A1 Keisuke Tateishi
A1 Kazuhiko Koike
YR 2018
UL http://gut.bmj.com/content/early/2018/02/06/gutjnl-2017-315193.abstract
AB 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.