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

Flurin Item, Stephan Wueest, Vera Lemos, Sokrates Stein, Fabrizio C. Lucchini, Rémy Denzler, Muriel C. Fisser, Tenagne D. Challa, Eija Pirinen, Youngsoo Kim, Silvio Hemmi, Erich Gulbins, Atan Gross, Lorraine A. O’Reilly, Markus Stoffel, Johan Auwerx and Daniel Konrad ()
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Flurin Item: University Children’s Hospital
Stephan Wueest: University Children’s Hospital
Vera Lemos: École Polytechnique Fédérale de Lausanne (EPFL)
Sokrates Stein: École Polytechnique Fédérale de Lausanne (EPFL)
Fabrizio C. Lucchini: University Children’s Hospital
Rémy Denzler: ETH Zurich
Muriel C. Fisser: ETH Zurich
Tenagne D. Challa: University Children’s Hospital
Eija Pirinen: École Polytechnique Fédérale de Lausanne (EPFL)
Youngsoo Kim: Ionis Pharmaceuticals Inc.
Silvio Hemmi: University of Zurich
Erich Gulbins: University of Duisburg-Essen
Atan Gross: The Weizmann Institute of Science
Lorraine A. O’Reilly: The Walter and Eliza Hall Institute of Medical Research
Markus Stoffel: ETH Zurich
Johan Auwerx: École Polytechnique Fédérale de Lausanne (EPFL)
Daniel Konrad: University Children’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00566-9

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DOI: 10.1038/s41467-017-00566-9

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