Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas

Background & Aims: Cholestatic liver injury results from the intrahepatic a ccumulation of toxic bile salts. Toxic bile salt-induced hepatocyte apoptos is in vitro is Fas dependent. The aim of this study was to ascertain if hep atocyte apoptosis in vivo during cholestasis is Fas dependent. Methods: Stu dies were performed in bile duct-ligated (BDL) Fas-deficient Ipr (lymphopro liferation) and wild-type mice. Results: Hepatocyte apoptosis was the predo minant mechanism of cell death as determined by terminal deoxynucleotidyl t ransferase-mediated deoxyuridine triphosphate nick-end labeling and trypan blue assays to quantitate apoptosis and necrosis. The mechanisms of hepatoc yte apoptosis were dependent on the presence or absence of the Fas receptor and the duration of BDL. After BDL of 3 days' duration, increased hepatocy te apoptosis occurred only in wild-type but not Ipr mice, indicating the ap optosis was Fas dependent. In contrast, after BDL of greater than or equal to 7 days, hepatocyte apoptosis also occurred in Ipr animals consistent wit h a Fas-independent mechanism of apoptosis. Hepatocyte apoptosis in BDL Ipr mice was associated with an increase in Bar expression and Bar association with mitochondria. Conclusions: During extrahepatic cholestasis, hepatocyt e apoptosis is mediated by Fas. However, in the absence of the Fas receptor , additional mechanisms of hepatocyte apoptosis occur. Inhibition of multip le apoptotic pathways is necessary to attenuate chronic cholestatic liver i njury.