A new study by the University of Illinois and collaborators reveals that excessive alcohol consumption disrupts the liver’s ability to regenerate by trapping liver cells in a dysfunctional “limbo” state, even after drinking stops. This occurs because inflammation interferes with RNA splicing, specifically due to the loss of a key splicing protein called ESRP2. As a result, critical proteins are misdirected inside the cell, impairing regeneration. The findings, published in Nature Communications, suggest that restoring ESRP2 function or targeting inflammatory pathways could offer new treatments for alcohol-associated liver disease, a condition responsible for nearly 3 million deaths annually. They write:

Excessive alcohol consumption can disrupt the liver’s unique regenerative abilities by trapping cells in limbo between their functional and regenerative states, even after a patient stops drinking, researchers at University of Illinois Urbana-Champaign and collaborators at Duke University and the Chan Zuckerberg Biohub Chicago describe in a new study.

This in-between state is a result of inflammation disrupting how RNA is spliced during the protein-making process, the researchers found, providing scientists with new treatment pathways to explore for the deadly disease. The researchers published their findings in the journal Nature Communications. […]

“We knew that the liver stops functioning and stops regenerating in patients with alcohol-related hepatitis and cirrhosis, even when a patient has discontinued consuming alcohol, but we didn’t know why,” said U. of I. biochemistry professor Auinash Kalsotra, who co-led the study with Duke University School of Medicine professor Anna Mae Diehl. “The only real life-saving treatment option once a patient reaches the liver failure stage in those diseases is transplantation. But if we understood why these livers were failing, maybe we could intervene.” […]

To verify that ESRP2 deficiency was a likely culprit, the researchers studied mice without the gene that produces ESRP2. They displayed similar liver damage and regeneration failure to that seen in patients with advanced alcohol-related hepatitis.

But why was ESRP2 missing from liver cells from patients with alcohol-related hepatitis? Upon investigation, the researchers found that liver support cells and immune cells, drawn to the liver tissue damaged by alcohol processing, released high amounts of inflammatory and growth factors. Those factors suppress ESRP2 production and activity. […]

“I’m hopeful these findings will become a launching pad for future clinical studies. We can use these misspliced RNAs as diagnostic markers or develop treatments that can curb the inflammation. And if we can correct the splicing defects, then maybe we can improve recovery and restore damaged livers,” Kalsotra said.

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