Bid-mediated apoptosis does not contribute to cholestatic liver injury following bile duct ligation

Death receptor-mediated hepatocyte apoptosis has been implicated in bile acid induced apoptosis of hepatocytes in vitro and in vivo. The BH3-interacting domain death agonist Bid is a critical mediator for apoptosis induced by activation of Fas and TNF-R1 death receptors in hepatocytes. Multiple studies have shown that bile acids induce Fas-dependent hepatocyte apoptosis in vitro providing a cellular mechanism for bile acid induced liver injury in vivo. More recent studies suggested that the mechanism of hepatocyte death is almost exclusively oncotic and that the protective effect in lpr mice most strikingly correlates with a reduced inflammatory response. In addition to these controversies, it is still unclear which down-stream targets of death receptors mediate the effect in rodent livers following BDL The aim of this study was therefore to elucidate the role of Bid in cholestatic liver injury. Overall survival and various aspects of liver injury were analyzed in WT and Bid-/- mice following BDL, a commonly used model to study obstructive cholestasis in mice. Liver injury was examined 3, 7 and 14 days after BDL. Loss of Bid did not affect the number of bile infarcts, serum AST values and animal survival. Processing of procaspase-3 and -9 and caspase-3 enzyme activities were not detectable in either group. Importantly, Bid-/- mice displayed the same pattern of TUNEL positive hepatocytes as WT controls following BDL and Bid-/- hepatocytes displayed the same sensitivity against DCA-induced apoptosis in vitro. In contrast to Fas-receptor deficient lpr mice, hepatic fibrosis and the inflammatory response was not affected by loss of Bid. Together, our data clearly show that Bid-mediated signaling does not play a role for BDL induced liver injury. Our findings strongly argue against selecting Bid as a therapeutic target in cholestasis and should therefore have implication for the development of new treatment strategies during bile acid induced liver injury.

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Bid apoptosis bile acids