New research indicates that alcohol-related liver disease can prevent the liver from repairing itself, even after alcohol consumption ceases. Scientists found that damaged liver cells become trapped in an abnormal state, unable to complete the regeneration process. This cellular stasis appears to be driven by inflammation that disrupts RNA splicing, a crucial step in protein synthesis.
Researchers from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago conducted the study. Their findings, published in *Nature Communications*, suggest new diagnostic and treatment approaches for severe alcohol-associated liver disease. The liver typically has a remarkable capacity for self-repair after injury or partial removal.
In healthy regeneration, liver cells temporarily revert to a fetal-like progenitor state, multiply, and then mature into fully functional liver cells. However, in alcohol-associated liver disease, this process breaks down. Diseased liver cells begin this transition but become trapped between their mature and progenitor states. This prevents them from functioning normally or completing regeneration.
The team examined liver samples from individuals with alcohol-associated hepatitis or cirrhosis. They observed widespread RNA mis-splicing across thousands of genes in these samples. This mis-splicing can alter protein function and localization within the cell. Specifically, a protein called ESRP2, which is essential for correct RNA splicing, was found to be deficient in alcohol-damaged liver cells.
Experiments with mice lacking ESRP2 showed similar patterns of liver injury and failed regeneration. The researchers traced the reduction of ESRP2 to inflammation caused by alcohol processing in the liver. Inflammatory and growth factors released by immune and liver support cells suppress ESRP2 production and activity. Blocking one of these inflammatory signals in laboratory cell cultures restored ESRP2 levels and normalized RNA splicing. This suggests that targeting inflammatory pathways could help restore the liver's regenerative capacity.
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