Item, FlurinWueest, StephanLemos, VeraStein, SokratesLucchini, Fabrizio C.Denzler, RemyFisser, Muriel C.Challa, Tenagne D.Pirinen, EijaKim, YoungsooHemmi, SilvioGulbins, ErichGross, AtanO'Reilly, Lorraine A.Stoffel, MarkusAuwerx, JohanKonrad, Daniel2017-11-082017-11-082017-11-08201710.1038/s41467-017-00566-9https://infoscience.epfl.ch/handle/20.500.14299/142067WOS:000409997500014Nonalcoholic 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.text::journal::journal article::research article