Dexamethasone decreases cholestatic liver injury via inhibition of intrinsic pathway with simultaneous enhancement of mitochondrial biogenesis

Abstract

Background: Mitochondria are known to be involved in cholestatic liver injury. We tested the hypothesis that glucocorticoids can modulate mitochondrial function to alleviate cholestatic liver injury.

Methods: A rat model of cholestasis was established by bile duct ligation (BDL), with a sham group receiving laparotomy without BDL, and a group receiving dexamethasone (DEX) treatment after BDL.

Results: The liver function including total bilirubin levels, alanine transaminase and aspartate transaminase activities was significantly improved in the DEX treatment group in comparison to the BDL group. There was a significant upregulation of liver peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial transcriptional factor A protein between 6 and 72 h was found in the DEX group. DEX treatment significantly down-regulated Bax, caspase 9 and caspase 3 expression induced by BDL at 24-72 h, but had little effect on the expression of caspase 8, Bcl(2,) Fas and Fas-FasL complex. Consequently, the number of apoptotic liver cells in the DEX group was significantly less than in the BDL group at 72 h.

Conclusion: Our results indicate that glucocorticoids decreases cholestatic liver injury within hours after BDL. Early glucocorticoids treatment can enhance the mitochondrial biogenesis and modulate the intrinsic but not extrinsic pathway of apoptosis following BDL.