Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000192728Publication status
publishedExternal links
Journal / series
Nature CommunicationsVolume
Pages / Article No.
Publisher
NatureOrganisational unit
03739 - Stoffel, Markus / Stoffel, Markus
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
More
Show all metadata