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Human Molecular Genetics, 2000, Vol. 9, No. 11 1597-1602
© 2000 Oxford University Press

Therapeutic liver repopulation in a mouse model of hypercholesterolemia

Claudia Mitchell, Alexandre Mignon+, Jacques E. Guidotti+, Sandrine Besnard1, Monique Fabre2, Nicolas Duverger3, David Parlier, Alain Tedgui1, Axel Kahn and Hélène Gilgenkrantz§

INSERM U129 ICGM, Université Paris V René Descartes, 24 rue du Fauboug Saint Jacques, 75014 Paris, France, 1INSERM U.141, Hôpital Lariboisière, 41 Boulevard de la chapelle, 75475 Paris Cedex 10, France, 2Hôpital du Kremlin Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France and 3Rhône-Poulenc Rorer—Gencell Division, Cardiovascular Department, Centre de Recherche de Vitry-Alfortville, 94403 Vitry sur Seine Cedex, France

Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active protein. We have described previously a model of selective repopulation of a normal liver by Fas/CD95-resistant hepatocytes, in which we achieved up to 16% hepato­cyte repopulation. In the present study, we investigated the therapeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) knockout mice were transplanted with Fas/CD95-resistant hepatocytes which constitutively express ApoE. Transplanted mice were submitted to weekly injections of non-lethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, we obtained up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol, which even fell to normal levels. Moreover, this secretion was sufficient to markedly reduce the progression of atherosclerosis. These results demonstrate the efficacy of this repopulation approach for correcting a deficiency in a protein secreted by the liver.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +33 1 44 41 24 04; Fax: +33 1 44 41 24 21; Email: gilgenkrantz@icgm.cochin.inserm.fr


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