NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis

Article

关键词: NONALCOHOLIC STEATOHEPATITIS;    SUPPRESSOR-CELLS;    HEPATOCELLULAR-CARCINOMA;    LIPID-METABOLISM;    LIVER-CANCER;    FATTY-ACIDS;    INFLAMMATION;    OBESITY;    NASH;    MICE;   

DOI  :  10.1038/nature16969

来源: SCIE

【 摘 要 】

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer(1-5). However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.

【 授权许可】

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