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    Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function

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    Author
    Item, F; Wueest, S; Lemos, V; Stein, S; Lucchini, FC; Denzler, R; Fisser, MC; Challa, TD; Pirinen, E; Kim, Y; ...
    Date
    2017-09-07
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    O'Reilly, Lorraine
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Item, F., Wueest, S., Lemos, V., Stein, S., Lucchini, F. C., Denzler, R., Fisser, M. C., Challa, T. D., Pirinen, E., Kim, Y., Hemmi, S., Gulbins, E., Gross, A., O'Reilly, L. A., Stoffel, M., Auwerx, J. & Konrad, D. (2017). Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function. NATURE COMMUNICATIONS, 8 (1), https://doi.org/10.1038/s41467-017-00566-9.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257151
    DOI
    10.1038/s41467-017-00566-9
    Abstract
    Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance. In line, hepatocyte-specific ablation of Fas improves mitochondrial function and ameliorates high-fat-diet-induced hepatic steatosis, glucose tolerance, and insulin resistance. Mechanistically, Fas impairs fatty acid oxidation via the BH3 interacting-domain death agonist (BID). Mice with genetic or pharmacological inhibition of BID are protected from Fas-mediated impairment of mitochondrial oxidation and hepatic steatosis. We suggest Fas as a potential novel therapeutic target to treat obesity-associated fatty liver and insulin resistance.Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.

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