Abstract
The deregulation of autophagy is involved in liver regeneration. Here, we investigated the role of autophagy in the regulation of liver regeneration after partial hepatectomy (PHx) and the development of pharmacological interventions for improved liver regeneration after PHx. We show that autophagy was activated in the early stages of liver regeneration following 70% PHx in vivo. Moreover, amiodarone was associated with a significant enhancement of autophagy, liver growth, and hepatocyte proliferation, along with reduced liver injury and the termination of liver regeneration due to decreased transforming growth factor-β1 expression after 70% PHx. The promotion of autophagy appeared to selectively increase the removal of damaged mitochondria. We also found that Atg7 knockdown or pretreatment with chloroquine aggravated the liver injury associated with 70% PHx and reduced liver growth and hepatocyte proliferation. Finally, amiodarone improved liver regeneration, survival, and liver injury after 90% PHx. In conclusion, our results indicate that autophagy plays an important role in mouse liver regeneration and that modulating autophagy with amiodarone may be an effective method of improving liver regeneration, increasing survival, and ameliorating liver injury following PHx.
Highlights
To determine the predominant factor of autophagy in liver regeneration following 70% PHx, we first examined the effect of autophagy on the dynamic changes that occur in the early phase of liver regeneration
We demonstrated that the enhancement of autophagy by amiodarone led to an increase in hepatocyte proliferation and liver growth and a decrease in the termination of liver regeneration after PHx
We demonstrated that inhibition of autophagy by Atg[7] knockdown or pretreatment with CQ resulted in a significant decrease in liver growth because hepatocyte proliferation and cell cycle progression were suppressed, and the termination of early-phase liver regeneration increased following PHx
Summary
Research has shown that autophagy plays a significant role in the pathogenesis of numerous human diseases and is induced by various stress conditions. Autophagy can serve as an effective defense mechanism against numerous pathological stresses, such as alcohol- and non-alcohol-induced fatty-liver conditions, hepatic alpha1-antitrypsin mutant proteins, and liver fibrosis[11,12,13,14,15,16,17]. Liver-specific Atg5-knockout mice exhibit reduced hepatocyte senescence and energy requirements during liver regeneration[19]. Amiodarone is a widely used, well-tolerated anti-arrhythmic drug in the clinic It can decrease calcium permeability, which can induce autophagy[21,22,23]. Our findings indicate that amiodarone is a promising intervention to promote autophagy, liver regeneration, hepatocyte proliferation and survival, and reduced liver damage following PHx
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