Delayed-onset caspase-dependent massive hepatocyte apoptosis upon fas activation in bak/bax-deficient mice


  • Potential conflict of interest: Nothing to report.

  • Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (to T. Takehara) and a Grant-in-Aid for Research on Hepatitis from the Ministry of Health, Labour, and Welfare of Japan.


The proapoptotic Bcl-2 family proteins Bak and Bax serve as an essential gateway to the mitochondrial pathway of apoptosis. When activated by BH3-only proteins, Bak/Bax triggers mitochondrial outer membrane permeabilization leading to release of cytochrome c followed by activation of initiator and then effector caspases to dismantle the cells. Hepatocytes are generally considered to be type II cells because, upon Fas stimulation, they are reported to require the BH3-only protein Bid to undergo apoptosis. However, the significance of Bak and Bax in the liver is unclear. To address this issue, we generated hepatocyte-specific Bak/Bax double knockout mice and administered Jo2 agonistic anti-Fas antibody or recombinant Fas ligand to them. Fas-induced rapid fulminant hepatocyte apoptosis was partially ameliorated in Bak knockout mice but not in Bax knockout mice, and was completely abolished in double knockout mice 3 hours after Jo2 injection. Importantly, at 6 hours, double knockout mice displayed severe liver injury associated with repression of XIAP, activation of caspase-3/7 and oligonucleosomal DNA breaks in the liver, without evidence of mitochondrial disruption or cytochrome c–dependent caspase-9 activation. This liver injury was not ameliorated in a cyclophilin D knockout background nor by administration of necrostatin-1, but was completely inhibited by administration of a caspase inhibitor after Bid cleavage. Conclusion: Whereas either Bak or Bax is critically required for rapid execution of Fas-mediated massive apoptosis in the liver, delayed onset of mitochondria-independent, caspase-dependent apoptosis develops even in the absence of both. The present study unveils an extrinsic pathway of apoptosis, like that in type I cells, which serves as a backup system even in type II cells. (HEPATOLOGY 2011 )