Experimental modulation of apoptosis: physiopathological and therapeutic targets

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.