Therapeutic liver repopulation in a mouse model of hypercholesterolemia

• Published in: Human molecular genetics Vol. 9; no. 11; pp. 1597 - 1602
• Main Authors: MITCHELL, C, MIGNON, A, GUIDOTTI, J. E, BESNARD, S, FABRE, M, DUVERGER, N, PARLIER, D, TEDGUI, A, KAHN, A, GILGENKRANTZ, H
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-07-2000; Oxford Publishing Limited (England)
• Subjects: Animals; Apolipoproteins E - blood; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Arteriosclerosis - pathology; Biological and medical sciences; CD95 antigen; Cell Transplantation; Cholesterol - blood; Disease Models, Animal; Disorders of blood lipids. Hyperlipoproteinemia; Fas ligand; Humans; hypercholesterolemia; Hypercholesterolemia - therapy; Lipoproteins - blood; Liver - cytology; Liver - metabolism; Liver - pathology; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Animal model; Liver; Rodentia; Transgenic animal; Metabolic diseases; Lipids; Hyperlipoproteinemia; Gene expression; Cholesterol; Vertebrata; Mammalia; Hypercholesterolemia; Hepatocyte; Mouse; Apolipoprotein E; Atherosclerosis; Apoptosis
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.11.1597

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.