Abstract
BackgroundCholestasis is characterized by an abnormal accumulation of bile acids and causes hepatocellular injury. Recent studies show that autophagy is involved in the pathophysiology of many liver diseases. The potential role of autophagy in preventing cholestatic hepatotoxicity, however, has rarely been investigated. The aim of this study was to examine whether autophagy is involved in the cholestatic hepatotoxicity.ResultsWe found that bile duct ligation (BDL) led to cholestatic liver injury and hepatocytic autophagy activation in the mice. Suppression of autophagy with Chloroquine (CQ) increased liver injury and hepatocytes apoptosis; while activation of autophagy by rapamycin reduced cholestasis hepatotoxicity. In L02 normal liver cells, Glycochenodeoxycholate (GCDC) treatment would induce autophagy. Inhibition of autophagy by CQ could promote GCDC-induced cell apoptosis. In contrast, rapamycin treatment could protect against GCDC-induced cell death. Furthermore, autophagy contributed to the liver cells survival via modulation of reactive oxygen species (ROS).ConclusionsThese findings indicate that autophagy protects against cholestasis induced liver injury and hepatocyte apoptosis by eliminating ROS accumulation. Our data suggest that enhancement of autophagy may be a therapeutic strategy to mitigate cholestatic liver injury.
Highlights
Cholestasis is a commonly clinical pathology of many diseases, which is characterized by an abnormal accumulation of bile acids
We investigated whether the autophagy machinery could be activated in liver injury induced by cholestasis; we hypothesized that autophagy contributes to the cell survival via reactive oxygen species (ROS) modulation in hepatocytes
Bile duct ligation promoted autophagy in the mouse liver In this part, we carried out a bile duct ligation (BDL) experiment to mimic the pathophysiogical process of cholestasis in vivo
Summary
Cholestasis is a commonly clinical pathology of many diseases, which is characterized by an abnormal accumulation of bile acids. The accumulation of p62 marks the dysfunctional autophagy which is not enough to process the damaged proteins bound to p62 [14]. It was found that autophagy plays important roles in cytoprotection against multiple pathological insults, including liver steatosis, liver injury, dyslipidemia in alcoholic, and nonalcoholic fatty liver conditions [17,18,19,20]. Cholestasis is characterized by an abnormal accumulation of bile acids and causes hepatocellular injury. Recent studies show that autophagy is involved in the pathophysiology of many liver diseases. The aim of this study was to examine whether autophagy is involved in the cholestatic hepatotoxicity
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