Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function
Fisser, Muriel C.
Challa, Tenagne D.
O'Reilly, Lorraine A.
- Journal Article
Rights / licenseCreative Commons Attribution 4.0 International
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
Journal / seriesNature Communications
Pages / Article No.
PublisherNature Publishing Group
Organisational unit03739 - Stoffel, Markus
02207 - Functional Genomics Center Zürich / Functional Genomics Center Zürich
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