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research article

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

Item, Flurin
•
Wueest, Stephan
•
Lemos, Vera
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2017
Nature Communications

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.

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Type
research article
DOI
10.1038/s41467-017-00566-9
Web of Science ID

WOS:000409997500014

Author(s)
Item, Flurin
•
Wueest, Stephan
•
Lemos, Vera
•
Stein, Sokrates
•
Lucchini, Fabrizio C.
•
Denzler, Remy
•
Fisser, Muriel C.
•
Challa, Tenagne D.
•
Pirinen, Eija  
•
Kim, Youngsoo
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Date Issued

2017

Publisher

Nature Research

Published in
Nature Communications
Volume

8

Start page

480

Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
NCEM  
Available on Infoscience
November 8, 2017
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/142067
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