Alcohol can seriously harm the liver by hindering its ability to repair itself. A recent study from the University of Illinois Urbana-Champaign, in collaboration with Duke University and the Chan Zuckerberg Biohub Chicago, reveals a key mechanism behind this issue. Heavy drinking disrupts RNA splicing, leaving liver cells stuck between working normally and regenerating, even after the person stops drinking.
This stalled state is linked to inflammation affecting how proteins are made. Published in Nature Communications, the findings highlight potential new treatment approaches for life-threatening liver diseases triggered by alcohol consumption, which claims around 3 million lives each year globally.
Biochemist Auinash Kalsotra, a co-lead of the study, explained, “We knew that fatty and inflamed livers struggled to regenerate, but we didn’t know why. Understanding these triggers could lead to new treatment strategies.”
For years, researchers have looked into how the liver regenerates after injury. They found that under normal conditions, liver cells can revert to a younger state, allowing them to multiply before maturing again. However, alcohol abuse disrupts this process. In examining liver samples from patients with alcohol-associated hepatitis or cirrhosis, scientists discovered that many cells couldn’t transition fully to a healthy state.
“They get stuck in a sort of limbo,” said researchers Ullas Chembazhi and Sushant Bangru. “They’re neither fully functional nor adequately regenerating, which adds pressure on other cells, eventually leading to liver failure.”
To understand why cells were trapped, the team analyzed RNA, which carries instructions for protein production. They used advanced RNA sequencing to find that many genes involved in liver function were incorrectly spliced, particularly affecting key proteins needed for good liver regeneration.
A significant finding was the deficiency of a protein called ESRP2. “This protein is crucial for proper RNA splicing,” Kalsotra said. In liver cells damaged by alcohol, ESRP2 levels dropped significantly, impairing RNA splicing and leading proteins to be misplaced within the cell, preventing proper function.
What’s worse is that inflammation triggered by alcohol metabolism appears to suppress ESRP2’s production. The team discovered that certain immune and liver support cells produce factors that limit ESRP2, worsening liver damage.
When researchers tested treatments that blocked these inflammatory factors, they found ESRP2 levels rebounded, and RNA splicing improved. “These results offer hope for future clinical studies,” Kalsotra emphasized. “If we can fix the RNA splicing problems, we might enhance recovery in damaged livers.”
This research not only helps unravel the biological effects of alcohol on the liver but also opens doors to new diagnostic tools and treatments. Understanding these molecular pathways can improve patient care and potentially save lives.
For the full study, see: “Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease”, published in Nature Communications.
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Alcohol,Inflammation,Liver,Molecular Biology,University of Illinois
