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    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 26934227
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    Publication Date: 2016-03-05
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786464/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Heikenwalder, Mathias -- Greten, Tim F -- ZIA BC011345-06/Intramural NIH HHS/ -- ZIABC011303/PHS HHS/ -- England -- Nature. 2016 Mar 10;531(7593):253-7. doi: 10.1038/nature16969. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland. ; Division of Oncology, Department of Medicine and Pathology, Stanford University, California 94305, USA. ; Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, USA. ; Institute of Virology, Technische Universitat Munchen/Helmholtz Zentrum Munchen, Munich 81675, Germany. ; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934227" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/immunology/metabolism/*pathology ; CD8-Positive T-Lymphocytes/immunology/pathology ; *Carcinogenesis/immunology/pathology ; Carcinoma, Hepatocellular/*immunology/metabolism/*pathology ; Case-Control Studies ; Choline/metabolism ; Diet ; Disease Models, Animal ; Genes, myc ; Hepatocytes/metabolism/pathology ; Humans ; Linoleic Acid/metabolism ; Lipid Metabolism ; Liver/immunology/pathology ; Liver Neoplasms/*immunology/metabolism/*pathology ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/pathology ; Non-alcoholic Fatty Liver Disease/*immunology/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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