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 (β-galactosidase, β-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 β-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 μg 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 μg) 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.
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Research Article|
March 13 2007
Lysosomes and Fas-mediated liver cell death
Robert Wattiaux;
Robert Wattiaux
1
1Laboratoire de Chimie Physiologique, URΦM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium
1To whom correspondence should be addressed (email robert.wattiaux@fundp.ac.be).
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Simone Wattiaux-De Coninck;
Simone Wattiaux-De Coninck
1Laboratoire de Chimie Physiologique, URΦM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium
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Jacqueline Thirion;
Jacqueline Thirion
1Laboratoire de Chimie Physiologique, URΦM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium
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Mańe-Christine Gasingirwa;
Mańe-Christine Gasingirwa
1Laboratoire de Chimie Physiologique, URΦM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium
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Michel Jadot
Michel Jadot
1Laboratoire de Chimie Physiologique, URΦM, FUNDP (Facultés Universitaires Notre-Dame de la Paix), 61 rue de Bruxelles, 5000 Namur, Belgium
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Publisher: Portland Press Ltd
Received:
November 21 2006
Accepted:
November 27 2006
Accepted Manuscript online:
November 27 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2007
Biochem J (2007) 403 (1): 89–95.
Article history
Received:
November 21 2006
Accepted:
November 27 2006
Accepted Manuscript online:
November 27 2006
Citation
Robert Wattiaux, Simone Wattiaux-De Coninck, Jacqueline Thirion, Mańe-Christine Gasingirwa, Michel Jadot; Lysosomes and Fas-mediated liver cell death. Biochem J 1 April 2007; 403 (1): 89–95. doi: https://doi.org/10.1042/BJ20061738
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