title: Delayed-onset caspase-dependent massive hepatocyte apoptosis upon Fas activation in Bak/Bax-deficient mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D017114:Liver Failure, Acute / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency* / Q000235:genetics; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D051023:BH3 Interacting Domain Death Agonist Protein; D007093:Imidazoles; D007211:Indoles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C507699:necrostatin-1; D020169:Caspases