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.
Literatur: Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann
SH, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation
of Fas. J Clin Invest 1999;103:137-145. Reinehr R, Graf D, Haussinger D. Bile salt-induced
hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine
phosphorylation. Gastroenterology 2003;125:839-853. Miyoshi H, Rust C, Roberts PJ,
Burgart LJ, Gores GJ. Hepatocyte apoptosis after bile duct ligation in the mouse involves
Fas. Gastroenterology 1999;117:669-677. Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo
TJ, Gores GJ. Fas enhances fibrogenesis in the bile duct ligated mouse: a link between
apoptosis and fibrosis. Gastroenterology 2002;123:1323-1330 Higuchi H, Miyoshi H,
Bronk SF, Zhang H, Dean N, Gores GJ. Bid antisense attenuates bile acid-induced apoptosis
and cholestatic liver injury. J Pharmacol Exp Ther 2001;299:866-873. Gujral JS, Liu
J, Farhood A, Jaeschke H. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr
mice after bile duct ligation. Hepatology 2004;40:998.
