2,

2, find more 29 Bak/Bax DKO mice were injected with 2 mg/kg necrostatin-1 at 2 hours after or 1 hour before Jo2 injection. The ALT levels at 6 hours after Fas stimulation were clearly elevated without a significant difference between the necrostatin-1 injection

group and the vehicle injection group (Fig. 6A and Supporting Fig. 4). We next examined the effect of CypD, which is a key molecule of mitochondrial permeability transition generated by Ca2+ overload and/or oxidative stress leading to necrotic cell death.14, 30 We injected Jo2 into CypD−/− mice with a Bak/Bax-deficient background (cypd−/−bak−/−baxflox/floxAlb-Cre) or control CypD+/+ or +/− littermates (cypd+/+ or +/−bak−/−baxflox/floxAlb-Cre). The ALT levels of CypD/Bak/Bax triple KO mice upon Fas stimulation were the same as those of control mice (Fig. 6B). These results indicate that liver injury in Bak/Bax deficiency induced by Fas stimulation was not dependent on the

necrotic pathway, at least that mediated by RIP kinase and/or CypD. Although cell death observed in Bak/Bax DKO mice appears to be apoptosis, the question arose of whether relatively weak caspase-3/7 activity compared with that observed in Bak KO mice is sufficient for inducing liver injury 6 hours after Fas simulation. To this end, Bak/Bax DKO mice were given 40 mg/kg Q-VD-Oph, a potent broad spectrum caspase inhibitor,31 2 hours after injection of Jo2. Western blot analysis revealed the existence of truncated Bid and cleaved caspase-8 in the liver 2 hours after Jo2 Selinexor mouse injection, demonstrating that caspase-8 had already been activated by this point (Fig. 7A). Administration of the caspase inhibitor at 2 hours completely blocked the elevation FER of serum ALT levels and hepatocellular apoptosis, as evidenced by liver histology and TUNEL staining 6 hours after Jo2 injection (Fig. 7B-D). Finally, we tried to analyze the survival rate of Bak/Bax DKO mice and control Bak KO mice when therapeutically injected with the caspase inhibitor 2 hours after

Jo2 injection. None of the Bak/Bax DKO mice showed lethal liver injury upon Jo2 injection, whereas half of the Bak KO mice died from severe liver injury (Fig. 7E). These findings suggest that Fas-induced liver injury in Bak/Bax deficiency was dependent on caspase activity, which could be fully negated by the caspase inhibitor. On the other hand, caspase activation in Bak KO mice was too high to be negated by the same dose of the caspase inhibitor. In the present study, we demonstrate that Bak KO, but not Bax KO, provides partial resistance to Fas-induced hepatocellular apoptosis in vivo. We demonstrated previously that Bak KO mice, but not Bax KO mice, showed resistance to apoptosis induced by Bcl-xL deficiency, which depended mainly on Bid activation.

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4. In blood and liver there was an accumulation of polyubiquitin con
5. We utilised Hoechst 33342 staining to demonstrate that H/ R induc