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.

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.

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
8.7K
Liver Regeneration01:24

Liver Regeneration

The liver is an important organ in vertebrates that plays an essential role in metabolism. It is also responsible for storing and redistributing nutrients such as carbohydrates, fats, and vitamins in the body. Additionally, the liver releases bile salts which are critical for digesting food and eliminating toxic metabolites from the body.
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...
4.5K
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
8.8K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
3.1K
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
15.4K