Liver Regeneration Challenges in Alcohol-Related Liver Disease

The liver is one of the few organs capable of self-regeneration after damage or partial removal. However, this ability is lost in cases of alcohol-related liver disease, which is a leading cause of liver-related deaths worldwide.

Challenges of Liver Regeneration in Alcohol-Related Liver Disease

Although the liver has regenerative capabilities, these are impaired in cases of alcohol-related hepatitis and cirrhosis. These health conditions lead to liver function failure, even after the patient stops consuming alcohol. In advanced stages of liver failure, the only real treatment option is liver transplantation.

Research has shown that liver cells need to reprogram their gene expressions to return to a state similar to embryonic stem cells, allowing them to proliferate and mature into fully functional cells. However, this mechanism is disrupted in alcohol-related liver disease.

The Role of RNA in Liver Regeneration Failure

Researchers discovered that liver cells damaged by alcohol begin the process of regeneration but do not complete it, remaining in a non-productive transitional state. These cells are neither fully functional adult cells nor proliferating stem cells, placing additional stress on the remaining cells and ultimately leading to liver failure.

The research team analyzed the proteins produced by liver cells and the RNA that carries the instructions for these proteins. They found that RNA is incorrectly spliced across a wide range of genes, affecting the key functions of the proteins.

The Role of ESRP2 Protein in Regenerative Processes

Researchers found that the ESRP2 protein plays a crucial role in correctly splicing RNA. In cases of liver damage due to alcohol, a deficiency in ESRP2 was observed, leading to incorrect splicing of proteins essential for liver regeneration.

Experiments on mice lacking the gene that produces ESRP2 showed liver damage and regeneration failure similar to that seen in patients with alcohol-related hepatitis.

Inflammatory Effects and Their Relation to ESRP2 Deficiency

Researchers found that liver-supporting cells and immune cells attracted to the damaged liver tissue release large amounts of inflammatory factors and growth factors, inhibiting the production and activity of ESRP2.

When liver cell cultures were treated with a molecule that blocks receptors for one of the inflammation-inducing factors, ESRP2 levels recovered, and splicing activities returned to normal, suggesting the potential to target this pathway as a treatment.

Conclusion

These discoveries provide a foundation for future clinical studies. Incorrectly spliced RNA can be used as diagnostic markers or to develop treatments that reduce inflammation. By correcting splicing defects, we may improve recovery and restore the function of damaged livers.