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Apoptotic cell death in the liver in response to activation of the Fas pathway has been implicated in human disease states as well as liver remodeling and tissue repair. C/EBPbeta, a member of the CCAAT enhancer binding protein family of bZIP transcription factors has been linked to both growth response and apoptotic targets in the liver, and, therefore, is a likely candidate for the regulation of apoptotic liver injury. We investigated differences in apoptotic cell death in the livers of C/EBPbeta-null mice using the Jo-2 agonistic anti-Fas antibody. Apoptotic injury was dramatically reduced in C/EBPbeta -/- livers as shown by a nearly 20-fold reduction in apoptotic hepatocytes 6 hours post-Jo-2 treatment in C/EBPbeta -/- hepatocytes compared with controls (P < .04) and reduced activation of caspase 3. Bid cleavage occurred in Jo-2 treated C/EBPbeta -/- livers indicating a block of Fas-induced injury distal to the death-inducing signaling complex. The level of the antiapoptotic protein bcl-x(L) was increased greater than tenfold in the mutant animals (P < .04), which can, at least in part, account for the protection from Fas-mediated apoptosis. In contrast, bcl-x(L) mRNA levels were unchanged. These observations link C/EBPbeta to Fas-induced hepatocyte apoptosis through a mechanism that likely involves translational or posttranslational regulation of bcl-x(L).
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