TY - JOUR T1 - CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity JF - Gut JO - Gut DO - 10.1136/gutjnl-2017-315193 SP - gutjnl-2017-315193 AU - Naoto Fujiwara AU - Hayato Nakagawa AU - Kenichiro Enooku AU - Yotaro Kudo AU - Yuki Hayata AU - Takuma Nakatsuka AU - Yasuo Tanaka AU - Ryosuke Tateishi AU - Yohko Hikiba AU - Kento Misumi AU - Mariko Tanaka AU - Akimasa Hayashi AU - Junji Shibahara AU - Masashi Fukayama AU - Junichi Arita AU - Kiyoshi Hasegawa AU - Hadassa Hirschfield AU - Yujin Hoshida AU - Yoshihiro Hirata AU - Motoyuki Otsuka AU - Keisuke Tateishi AU - Kazuhiko Koike Y1 - 2018/02/06 UR - http://gut.bmj.com/content/early/2018/02/06/gutjnl-2017-315193.abstract N2 - 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. ER -