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

Nat Commun. 2017 Sep 7;8(1):480. doi: 10.1038/s41467-017-00566-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Fatty Acids / metabolism
  • Insulin Resistance
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Mice, Transgenic
  • Mitochondria, Liver / metabolism*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Triglycerides / metabolism
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • Fas Ligand Protein
  • Fas protein, mouse
  • Fasl protein, mouse
  • Fatty Acids
  • Triglycerides
  • fas Receptor