Abstract
Acute liver failure (ALF) is an inflammation-mediated hepatocellular injury process associated with cellular autophagy. However, the mechanism by which autophagy regulates ALF remains undefined. Herein, we demonstrated that Eva1a (eva-1 homolog A)/Tmem166 (transmembrane protein 166), an autophagy-related gene, can protect mice from ALF induced by d-galactosamine (D-GalN)/lipopolysaccharide (LPS) via autophagy. Our findings indicate that a hepatocyte-specific deletion of Eva1a aggravated hepatic injury in ALF mice, as evidenced by increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), myeloperoxidase (MPO), and inflammatory cytokines (e.g., TNFα and IL-6), which was associated with disordered liver architecture exhibited by Eva1a−/− mouse livers with ALF. Moreover, we found that the decreased autophagy in Eva1a−/− mouse liver resulted in the substantial accumulation of swollen mitochondria in ALF, resulting in a lack of ATP generation, and consequently hepatocyte apoptosis or death. The administration of Adeno-Associated Virus Eva1a (AAV-Eva1a) or antophagy-inducer rapamycin increased autophagy and provided protection against liver injury in Eva1a−/− mice with ALF, suggesting that defective autophagy is a significant mechanism of ALF in mice. Collectively, for the first time, we have demonstrated that Eva1a-mediated autophagy ameliorated liver injury in mice with ALF by attenuating inflammatory responses and apoptosis, indicating a potential therapeutic application for ALF.
Highlights
Acute liver failure (ALF) is a clinical syndrome that involves hepatocellular apoptosis and necrosis[1]
Our results show that the Eva1a−/− mice exhibited more severe liver injury following ALF, which was accompanied by impaired autophagy
Similar to Eva1a expression, a tendency was observed for the key autophagy proteins, Atg[], Atg16l1, and Beclin[1], to change during the same time period in mice with ALF (Fig. 1f, g)
Summary
Acute liver failure (ALF) is a clinical syndrome that involves hepatocellular apoptosis and necrosis[1]. The nature of ALF has been widely studied, the mechanisms are not completely understood. The co-administration of the hepatocyte-specific transcriptional inhibitor, D-galactosamine (D-GalN), and the endotoxin, lipopolysaccharide (LPS) is an established model for studying ALF in mice. This model has been widely used to study the mechanisms of ALF pathogenesis and identify novel therapeutic drugs[5]. Dgalactosamine (D-GalN) is a specific hepatotoxic agent which leads to a depletion of hepatic UTP, followed by the cessation of macromolecule biosynthesis, followed by alterations in the structure and function of the plasma membrane, eventually causing cellular damage and death. Upon stimulation with LPS in this model, Kupffer cells and infiltrating
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