The present study therefore demonstrates that hepatocytes can act as type I cells in the absence of Bak and Bax independent of the strength of DISC formation or signals from microenvironments. The question arises of why hepatocytes can act as type I cells where the levels of DISC formation

or caspase-8 activation may be insufficient to induce activation of downstream caspases. Recently, Jost et al.27 reported a discriminating role of XIAP between type I and type II cells; in type II cells, the levels of XIAP expression increased after Fas stimulation but decreased in type I cells. In agreement with this report, XIAP expression was up-regulated at 3 hours in both Bak KO and Bak/Bax DKO

livers. Interestingly, this XIAP up-regulation disappeared at 6 hours after PD-0332991 nmr Jo2 injection in Bak/Bax DKO mice. Because XIAP is a potent inactivator of caspase-3, -7, and -9 processing, repression of XIAP may be one reason why hepatocytes can act as type I cells at this time point. Previous studies learn more have reported that liver endothelial cells express Fas receptor and have suggested that apoptosis of these cells may participate in the liver damage in mice receiving Jo2 antibody, especially in the case of high-dose administration.35 However, we did not find liver injury in the sinusoidal hemorrhage in Bak/Bax DKO mice at 3 hours after Jo2 injection, which is the time point when Bak KO mice developed it (Fig. 3C). Together with the fact that Bax, but not Bak, was active in liver nonparenchymal cells in our Bak/Bax DKO mice, as was the case in Bak KO mice (Fig. 3A), we speculate that Bak-deficient sinusoidal cells could not contribute much to liver injury at 3 hours after Jo2 injection (1.5 or 0.5 mg/kg). Recently, a pan-caspase inhibitor Carnitine palmitoyltransferase II was reported to reduce hepatic damage in liver transplant recipients

and patients with chronic hepatitis C in clinical trials.36, 37 For treatment of fulminant liver injury, caspase inhibitors seem to be attractive drugs. However, the present study demonstrates that Fas-induced apoptotic signals could be efficiently amplified through the mitochondrial pathway, leading to high lethality even if caspase inhibitor was administered 2 hours after Jo2 injection. In contrast, administration of the same dose of the caspase inhibitor was able to fully block hepatocyte apoptosis and lethality in Bak/Bax DKO mice. From a clinical point of view, when using caspase inhibitors to prevent fulminant liver failure, concomitant inactivation of the mitochondrial amplification loop may be required. In conclusion, the extrinsic pathway of apoptosis exists in hepatocytes and causes late onset of lethal liver failure in the absence of Bak and Bax independent of the strength of Fas ligation.