279 Decrease the Cholestasis Injury is Via Inhibition of Intrinsic Pathway with Enhanced Mitochondrial Biogenesis

Abstract

Background: Mitochondria are known to involve in cholestatic liver injury. The impaired mitochondrial biogenesis and intrinsic apoptosis pathway is activated associated with oxidative damage. Aims: We further test the involvement of key mitochondrial apoptotic regulators in response to the early stage of corticosteroids on cholestasis and the possible protective mechanistic roles of steroid in this liver damage animal model. Methods: A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneously creation of the sham group receiving laparotomy without BDL, and dexamethasone (DEX) after BDL as a treatment. The expression of proteins involved in the activation of apoptotic pathways was analyzed by western blotting. Apoptosis of liver cells was examined by TUNEL stain. Results: The apoptotic liver cells appeared in large amounts in the rat liver by 72h after BDL in the apoptotic markers and could be recovered significantly after DEX treatment by 72h. A significant upregulation of liver peroxisome proliferators-activated receptor γ coactivator-1α and mitochondrial transcriptional factor A protein from 24 to 72h was found in the DEX group. After DEX treatment, significant down-regulated Bax, caspase 9 and caspase 3 at 24-72h, but not caspase 8, Bcl2, Fas and Fas-Fas L complex in the liver homogenates of BDL rats was found. The activation of NFκB was inhibited by DEX treatment. Conclusions: Our results indicate that early DEX treatment reverses impaired mitochondrial biogenesis within hours after BDL, via modulating of intrinsic apoptosis pathway. NFκB activity is involved in the process of liver cell damage.