Alcohol Damage Traps Liver Cells Mid-Repair, Study Finds

Excessive alcohol use can disrupt one of the liver's most remarkable abilities: repairing itself after injury. Researchers at the University of Illinois Urbana-Champaign, Duke University and the Chan Zuckerberg Biohub Chicago have found that alcohol-related damage can leave liver cells trapped in an abnormal middle state, unable to function normally or finish regenerating even after a person stops drinking. The findings, published in Nature Communications, could point toward new ways to diagnose and treat severe alcohol-associated liver disease.

The liver is unusual among major organs because it can regenerate after significant damage: surviving cells temporarily revert toward a less specialized, fetal-like "progenitor" state, multiply, and then mature again to rebuild lost tissue. That ability breaks down in alcohol-associated liver disease, the leading cause of liver-related death worldwide, linked to roughly 3 million deaths a year. The study was co-led by University of Illinois biochemistry professor Auinash Kalsotra and Duke University School of Medicine professor Anna Mae Diehl, who had long known that livers stop functioning and regenerating in alcohol-related hepatitis and cirrhosis, even after a patient stops drinking, but did not know why.

Comparing healthy liver tissue with samples from people with alcohol-associated hepatitis or cirrhosis, obtained from Johns Hopkins University Hospital through a National Institute on Alcohol Abuse and Alcoholism initiative, the researchers found diseased cells had started moving from their mature state toward the regenerative state but could not complete the transition, becoming trapped in an unproductive middle state. As more cells get trapped, fewer remain for the liver's normal work, pressuring the remaining healthy cells and raising their own risk of becoming trapped too.

The team traced the problem to inflammation that disrupts RNA splicing, the process of cutting and rejoining RNA molecules that carry genetic instructions from DNA to the machinery that builds proteins. Using deep RNA sequencing, the researchers found RNA was mis-spliced across thousands of genes in alcohol-related liver disease, affecting protein functions, including the instructions that tell proteins where inside a cell to go.

The researchers identified one likely driver: low levels of a protein called ESRP2, which normally binds to RNA and helps ensure it is spliced correctly. Liver cells damaged by alcohol had a deficiency of ESRP2.