NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
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DOI：
10.1038/nature16969
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发表时间：
2016-03-10
期刊：
影响因子：
64.8
通讯作者：
Greten TF
中科院分区：
文献类型：
--
作者：
Ma C;Kesarwala AH;Eggert T;Medina-Echeverz J;Kleiner DE;Jin P;Stroncek DF;Terabe M;Kapoor V;ElGindi M;Han M;Thornton AM;Zhang H;Egger M;Luo J;Felsher DW;McVicar DW;Weber A;Heikenwalder M;Greten TF
肝细胞癌（HCC）是癌症相关死亡的第二大常见原因。非酒精性脂肪性肝病（NAFLD）影响了很大一部分美国人口，被认为是肝癌的代谢易感性。然而，适应性免疫反应在nafld促进的HCC中的作用在很大程度上是未知的。在这里，我们发现NAFLD中脂质代谢失调导致肝内CD4+而非CD8+ T淋巴细胞的选择性损失，从而加速肝癌的发生。我们还发现CD4+ T淋巴细胞比CD8+ T淋巴细胞具有更大的线粒体质量，并产生更高水平的线粒体源性活性氧（ROS）。亚油酸是NAFLD中积累的一种脂肪酸，它对线粒体功能的破坏比棕榈酸等其他游离脂肪酸造成更多的氧化损伤，并介导肝内CD4+ T淋巴细胞的选择性损失。体内阻断ROS可逆转nafld诱导的肝脏CD4+ T淋巴细胞减少和延迟nafld促进的HCC。我们的研究结果在脂质失调和抗肿瘤监测受损之间提供了意想不到的联系。
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 a metabolic predisposition to liver cancer . However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here, we show 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 found 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-tumor surveillance.