Autophagy and apoptosis in liver injury.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang K
PROVIDER: S-EPMC4614283 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.
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Project description:Background and Aims: Acute liver failure (ALF) is a type of liver injury that is caused by multiple factors and leads to severe liver dysfunction; however, current treatments for ALF are insufficient. Magnesium isoglycyrrhizinate (MgIG), a novel glycyrrhizin extracted from the traditional Chinese medicine licorice, has a significant protective effect against concanavalin A (ConA)-induced liver injury, but its underlying therapeutic mechanism is unclear. Hence, this study aims to explore the potential therapeutic mechanism of MgIG against ConA-induced immune liver injury. Methods: ConA (20 mg/kg, i. v.) was administered for 12 h to construct an immune liver injury model, and the treatment group was given MgIG (30 mg/kg, i. p.) injection 1 h in advance. Lethality, liver injury, cytokine levels, and hepatocyte death were evaluated. The level of autophagy was evaluated by electron microscopy, RT-PCR and western blotting, and hepatocyte death was assessed in vitro by flow cytometry. Results: MgIG significantly increased the survival rate of mice and ameliorated severe liver injury mediated by ConA. The decrease in the number of autophagosomes, downregulation of LC3b expression and upregulation of p62 expression indicated that MgIG significantly inhibited ConA-induced autophagy in the liver. Reactivation of autophagy by rapamycin (RAPA) reversed the protective effect of MgIG against ConA-induced liver injury. Compared with MgIG treatment, activation of autophagy by RAPA also promoted the expression of liver inflammation markers (IL-1β, IL-6, TNF-α, CXCL-1, CXCL-2, CXCL-10, etc.) and hepatocyte death. In vitro experiments also showed that MgIG reduced ConA-induced hepatocyte death but did not decrease hepatocyte apoptosis by inhibiting autophagy. Conclusion: MgIG significantly ameliorated ConA-induced immune liver injury in mice by inhibiting autophagy. This study provides theoretical support for the ability of MgIG to protect against liver injury in clinical practice.
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