Lysosomes and Fas-mediated Liver Cell Death.
From: Laboratoire de Chimie Physiologique, URPhiM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium. robert.wattiaux@fundp.ac.be
The Biochemical journal
- Publish Date: Apr 2007
- ISSN: 1470-8728
- Volume: 403
- Issue: 1
- Pages: 89-95
- Medium: Internet
- Language: English
- Citation (JAMA): Wattiaux Robert, Wattiaux-de Coninck Simone, Thirion Jacqueline, et al. Lysosomes and Fas-mediated Liver Cell Death.. Biochem. J. Apr 2007;403:89-95
Abstract
A number of studies, mostly performed ex vivo, suggest that lysosomes are involved in apoptosis as a result of a release of their cathepsins into the cytosol. These enzymes could then contribute to the permeabilization of the outer mitochondrial membrane; they could also activate effector caspases. The present study aims at testing whether the membrane of liver lysosomes is disrupted during Fas-mediated cell death of hepatocytes in vivo, a process implicated in several liver pathologies. Apoptosis was induced by injecting mice with aFas (anti-Fas antibody). The state of lysosomes was assessed by determining the proportion of lysosomal enzymes (beta-galactosidase, beta-glucuronidase, cathepsin C and cathepsin B) present in homogenate supernatants, devoid of intact lysosomes, and by analysing the behaviour in differential and isopycnic centrifugation of beta-galactosidase. Apoptosis was monitored by measuring caspase 3 activity (DEVDase) and the release of sulfite cytochrome c reductase, an enzyme located in the mitochondrial intermembrane space. Results show that an injection of 10 microg of aFas causes a rapid and large increase in DEVDase activity and in unsedimentable sulfite cytochrome c reductase. This modifies neither the proportion of unsedimentable lysosomal enzyme in the homogenates nor the behaviour of lysosomes in centrifugation. Experiments performed with a lower dose of aFas (5 microg) indicate that unsedimentable lysosomal hydrolase activity increases in the homogenate after injection but with a marked delay with respect to the increase in DEVDase activity and in unsedimentable sulfite cytochrome c reductase. Comparative experiments ex vivo performed with Jurkat cells show an increase in unsedimentable lysosomal hydrolases, but much later than caspase 3 activation, and a release of dipeptidyl peptidase III and DEVDase into culture medium. It is proposed that the weakening of lysosomes observed after aFas treatment in vivo and ex vivo results from a necrotic process that takes place late after initiation of apoptosis.
Mesh Headings (Keywords): Animals, Antigens, CD95, Caspase 3, Cell Death, Cell Fractionation, Female, Hepatocytes, Humans, Jurkat Cells, Liver, Lysosomes, Mice, Mice, Inbred Strains
Check for Full Text / PubMed Unique Identifier (PMID): 17129211
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