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

Item, F; Wueest, S; Lemos, V; Stein, S; Lucchini, FC; Denzler, R; Fisser, MC; Challa, TD; Pirinen, E; Kim, Y; Hemmi, S; Gulbins, E; Gross, A; O&#39;Reilly, LA; Stoffel, M; Auwerx, J; Konrad, D

Author(s): Item, F; Wueest, S; Lemos, V; Stein, S; Lucchini, FC; Denzler, R; Fisser, MC; Challa, TD; Pirinen, E; Kim, Y; Hemmi, S; Gulbins, E; Gross, A; O'Reilly, LA; Stoffel, M; Auwerx, J; Konrad, D;
Details: Publication Year 2017-09-07,Volume 8,Issue #1,Page 480
Journal Title: Nature Communications
Publication Type: Journal Article
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.
Publisher: Springer Nature
Research Division(s): Molecular Genetics Of Cancer
PubMed ID: 28883393
Publisher's Version: https://doi.org/10.1038/s41467-017-00566-9
Open Access at Publisher's Site: http://www.nature.com/articles/s41467-017-00566-9
NHMRC Grants: NHMRC/361646,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-10-16 01:59:59

Last Modified: 2017-10-17 08:06:06