Therapeutic liver repopulation in a mouse model of hypercholesterolemia

Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active pr otein, 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 ther apeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) k nockout mice were transplanted with Fas/CD95-resistant hepatocytes which co nstitutively express ApoE, Transplanted mice were submitted to weekly injec tions 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 pl asma cholesterol, which even fell to normal levels. Moreover, this secretio n was sufficient to markedly reduce the progression of atherosclerosis, The se results demonstrate the efficacy of this repopulation approach for corre cting a deficiency in a protein secreted by the liver.