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

作者：Ma, Chi; Kesarwala, Aparna H.; Eggert, Tobias; Medina-Echeverz, Jose; Kleiner, David E.; Jin, Ping; Stroncek, David F.; Terabe, Masaki; Kapoor, Veena; ElGindi, Mei; Han, Miaojun; Thornton, Angela M.; Zhang, Haibo; Egger, Michele; Luo, Ji; Felsher, Dean W.; McVicar, Daniel W.; Weber, Achim; Eikenwalder, Mathias H.; Greten, Tim F.^*

来源：Nature, 2016, 531(7593): 253-+.

DOI：10.1038/nature16969

• NONALCOHOLIC STEATOHEPATITIS
• SUPPRESSOR-CELLS
• HEPATOCELLULAR-CARCINOMA
• LIPID-METABOLISM
• LIVER-CANCER
• FATTY-ACIDS
• INFLAMMATION
• OBESITY
• NASH
• MICE

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.

• 出版日期2016-3-10