Hyperlipidemias: Mitchell C

Mitchell C, Mallet V, Guidotti JE, Mignon A, Couton D, Kahn A, Gilgenkrantz H. · Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaires, U567 INSERM, CNRS 8101 UMR, Université R. Descartes, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France. · J Soc Biol. · Pubmed #16471264 No free full text.

Abstract: In the liver, the importance of apoptosis is not only evident during development and homeostasis of the biliary tree but plays also a prominent role in liver pathogenesis. Ligand binding to cell surface death receptors such as Fas activates the extrinsic pathway. This pathway predominates in autoimmune liver diseases, viral hepatitis, liver allograft rejection. Hepatocyte apoptosis is also significantly increased in patients with alcoholic hepatitis and nonalcoholic steatohepatitis and correlates with disease severity and hepatic fibrosis. We have used this specific susceptibility of the liver to apoptosis to develop two different approaches: 1) a cell therapy strategy based on a survival advantage to an apoptotic stimulus conferred to transplanted hepatocytes and 2) a new model of hepatocyte conditional ablation based on a controlled activation of the cell death program.

Mitchell C, Mignon A, Guidotti JE, Besnard S, Fabre M, Duverger N, Parlier D, Tedgui A, Kahn A, Gilgenkrantz H. · INSERM U129 ICGM, Université Paris V René Descartes, Paris, France. · Hum Mol Genet. · Pubmed #10861286 links to  free full text

Abstract: 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.