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Ma, C.* ; Kesarwala, A.H.* ; Eggert, T.* ; Medina-Echeverz, J.* ; Kleiner, D.E.* ; Jin, P.* ; Stroncek, D.F.* ; Terabe, M.* ; Kapoor, V.* ; ElGindi, M.* ; Han, M.* ; Thornton, A.M.* ; Zhang, H.* ; Egger, M.* ; Luo, J.* ; Felsher, D.W.* ; McVicar, D.W.* ; Weber, A.* ; Heikenwälder, M. ; Greten, T.F.*

NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis.

Nature 531, 253-257 (2016)
Postprint DOI PMC
Open Access Green
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. 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fatty Liver-disease; Nonalcoholic Steatohepatitis; Hepatocellular-carcinoma; Suppressor-cells; Lipid-metabolism; Mice; Cancer; Obesity; Hepatocytes; Inflammation
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 531, Issue: 7593, Pages: 253-257 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-551600-001
DOI 10.1038/nature16969
WOS ID WOS:000371665100046
PubMed ID 26934227
Erfassungsdatum 2016-03-07
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