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Published on: November 27, 2019
Mir-24 regulates hepatocyte apoptosis via BIM during acute liver failure
Zhiwen Feng1, Zhi Li1, Deming Zhu1
1Laboratory of Liver Transplantation, Nanjing Medical UniversityNanjing, China.
Abstract:
Acuteliver failure (ALF) has a high mortality rate and is characterized by massive hepatocyte destruction. Although microRNAs (miRNAs) play an important role in manyliver diseases, the role of miRNAs in ALF development is unknown. In this study, the murine ALF model was induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (D-GalN/LPS). Compared with saline-treated mice, miR-24 was distinctly down-regulated post D-GalN/LPS challenge in vivo and D-galactosamine/tumor necrosis factor (D-GalN/TNF) challenge in vitro, which was confirmed by quantitative real-time polymerase chain reaction. Meanwhile, the mRNA and protein levels of the BH3-only-domain-containing protein BIM were upregulated after challenge both in vivo and in vitro. Previous studies have demonstrated that hepatocyte apoptosis is a distinguishing feature of D-GalN/LPS-associated liver failure. In this study, D-GalN/LPS-challenged mice showed higher alanine aminotransferase and aspartate aminotransferase levels, more severe liver damage, increased numbers of apoptotic hepatocytes and higher levels of caspase-3 compared with saline-treated mice. In D-GalN/TNF-treated BNLCL2 cells, miR-24 overexpression attenuated apoptosis.Furthermore, miR-24 overexpression reduced BIM mRNA and protein levels in vitro. Taken together, these findings demonstrate that miR-24 regulates hepatocyte apoptosis via BIM during ALF development, suggesting that miR-24 is a novel onco-miRNA that may provide potential therapeutic targets for ALF.
Insights
MicroRNA-24 (miR-24) is down-regulated in acute liver failure (ALF), a condition marked by hepatocyte death. This study shows miR-24 regulates liver cell apoptosis via BIM, offering potential therapeutic targets for ALF.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Acute liver failure (ALF) is a critical condition with high mortality due to extensive hepatocyte destruction.
- The role of microRNAs (miRNAs) in ALF pathogenesis remains largely unexplored.
- Hepatocyte apoptosis is a key characteristic of ALF, particularly in models induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS).
Purpose of the Study:
- To investigate the role of specific microRNAs in the development of ALF.
- To elucidate the molecular mechanisms underlying hepatocyte apoptosis in ALF.
- To identify potential miRNA-based therapeutic targets for ALF.
Main Methods:
- Induction of a murine ALF model using D-GalN/LPS and in vitro models with D-GalN/TNF.
- Quantitative real-time polymerase chain reaction (qRT-PCR) to measure miR-24 expression.
- Assessment of hepatocyte apoptosis markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), cleaved caspase-3, and BIM expression.
Main Results:
- miR-24 was significantly down-regulated in both in vivo and in vitro ALF models.
- Hepatocyte apoptosis, liver damage, and levels of ALT, AST, and caspase-3 were elevated in ALF models.
- Overexpression of miR-24 attenuated hepatocyte apoptosis and reduced BIM mRNA and protein levels in vitro.
Conclusions:
- miR-24 plays a crucial role in regulating hepatocyte apoptosis during ALF development by targeting BIM.
- Down-regulation of miR-24 contributes to ALF pathogenesis.
- miR-24 represents a novel oncomiR and a potential therapeutic target for acute liver failure.
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