期刊
GUT
卷 67, 期 8, 页码 1493-1504出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2017-315193
关键词
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资金
- Uehara Memorial Foundation
- JSPS KAKENHI [15K19313]
- Viral Hepatitis Research Foundation of Japan
- Daiichi Sankyo Foundation of Life Science
- Bristol-Myers Squibb Research Grant
- Program for Basic and Clinical Research on Hepatitis from Japan Agency for Medical Research and Development, AMED [JP17fk0210304]
- AMED-CREST [JP17gm0710004]
- NATIONAL CANCER INSTITUTE [P30CA196521] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK099558] Funding Source: NIH RePORTER
- Grants-in-Aid for Scientific Research [15K19313] Funding Source: KAKEN
Objective Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and nonalcoholic 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 he 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 beta-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 STAT 3 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.
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