AMPK-mTOR-ULK1-mediated autophagy protects carbon tetrachloride-induced acute hepatic failure by inhibiting p21 in rats

Autophagy is a lysosomal-dependent degradation pathway in eukaryotic cells. Recent studies have reported that autophagy can facilitate the activation of hepatic stellate cells (HSCs) and fibrogenesis of the liver during long-term carbon tetrachloride (CCl(4)) exposure. However, little is known about the role of autophagy in CCl(4)-induced acute hepatic failure (AHF). This study aimed to identify whether modulation of autophagy can affect CCl(4)-induced AHF and evaluate the upstream signaling pathways mediated by CCl(4)-induced autophagy in rats. The accumulation of specific punctate distribution of endogenous LC3-II, increased expression of LC3-II, Atg5, and Atg7 genes/proteins, and decreased expression of p62 gene were observed after acute liver injury was induced by CCl(4) in rats, indicating that CCl(4) resulted in a high level of autophagy. Moreover, loss of autophagic function by using chloroquine (CQ, an autophagic inhibitor) aggravated liver function, leading to increased expression of p21 (a cyclin-dependent kinase inhibitor) in CCl(4)-treated rats. Furthermore, the AMPK-mTORC1-ULK1 axis was found to serve a function in CCl(4)-induced autophagy. These results reveal that AMPK-mTORC1-ULK1 signaling-induced autophagy has a protective role in CCl(4)-induced hepatotoxicity by inhibiting the p21 pathway. This study suggests a useful strategy aimed at ameliorating CCl(4)-induced acute hepatotoxicity by autophagy.