Fas-induced apoptosis in mouse hepatocytes is dependent on C/EBP beta

Apoptotic cell death in the liver in response to activation of the Fas path way has been implicated in human disease states as well as liver remodeling and tissue repair. C/EBP beta, a member of the CCAAT enhancer binding prot ein family of bZIP transcription factors has been linked to both growth res ponse and apoptotic targets in the liver, and, therefore, is a likely candi date for the regulation of apoptotic liver injury. We investigated differen ces in apoptotic cell death in the livers of C/EBP beta -null mice using th e Jo-2 agonistic anti-Fas antibody. Apoptotic injury was dramatically reduc ed in C/EBP beta -/- livers as shown by a nearly 20-fold reduction in apopt otic hepatocytes 6 hours post-Jo-2 treatment in C/EBP beta -/- hepatocytes compared with controls (P < .04) and reduced activation of caspase a. Bid c leavage occurred in Jo-2 treated C/EBP beta -/- livers indicating a block o f Fas-induced injury distal to the death-inducing signaling complex. The le vel of the antiapoptotic protein bcl-x(L) was increased greater than tenfol d 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 lev els were unchanged. These observations link C/EBP beta to Fas-induced hepat ocyte apoptosis through a mechanism that likely involves translational or p osttranslational regulation of bcl-x(L).