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

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.

Induction of the proapoptotic tumor suppressor gene Cell Adhesion Molecule 1 by chemotherapeutic agents is repressed in therapy resistant acute myeloid leukemia.

Even though a large proportion of patients with acute myeloid leukemia (AML) achieve a complete remission upon initial therapy, the majority of them eventually relapse with resistant disease. Overexpression of the gene coding for the transcription factor Ecotropic Virus Integration site 1 (EVI1) is associated with rapid disease recurrence and shortened survival. We therefore sought to identify EVI1 target genes that may play a role in chemotherapy resistance using a previously established in vitro model system for EVI1 positive myeloid malignancies. Gene expression microarray analyses uncovered the Cell Adhesion Molecule 1 (CADM1) gene as a candidate whose deregulation by EVI1 may contribute to drug refractoriness. CADM1 is an apoptosis inducing tumor suppressor gene that is inactivated by methylation in a variety of tumor types. In the present study we provide evidence that it may play a role in chemotherapy induced cell death in AML: CADM1 was induced by drugs used in the treatment of AML in a human myeloid cell line and in primary diagnostic AML samples, and its experimental expression in a cell line model increased the proportion of apoptotic cells. CADM1 up-regulation was abolished by ectopic expression of EVI1, and EVI1 expression correlated with increased CADM1 promoter methylation both in a cell line model and in primary AML cells. Finally, CADM1 induction was repressed in primary samples from AML patients at relapse. In summary, these data suggest that failure to up-regulate CADM1 in response to chemotherapeutic drugs may contribute to therapy resistance in AML.