Impact of Excessive Alcohol Consumption on Liver Regeneration
Excessive alcohol consumption can significantly disrupt the liver’s remarkable regenerative abilities. This disruption is caused by cellular changes that trap liver cells in an intermediate state between functionality and regeneration, even after individuals cease drinking, as detailed in a recent study conducted by researchers at the University of Illinois Urbana-Champaign, in collaboration with Duke University and the Chan Zuckerberg Biohub Chicago.
Understanding the Cellular Mechanism
This intermediate cellular state stems from inflammation that interferes with RNA splicing during the protein synthesis process. The findings provide novel avenues for therapeutic intervention for alcohol-associated liver disease, which is a leading cause of liver-related mortality globally, resulting in approximately 3 million deaths each year. The study appears in the journal Nature Communications.
The Liver’s Regenerative Abilities
The liver possesses a remarkable capacity to regenerate following damage or partial removal. However, this ability diminishes in individuals suffering from alcohol-associated liver disease. “We understood that the liver ceases to function and regenerate in patients with alcohol-related hepatitis and cirrhosis, even after they stop consuming alcohol,” stated U. of I. biochemistry professor Auinash Kalsotra, co-leader of the study. “Currently, the primary life-saving treatment option at the liver failure stage is transplantation. Understanding the mechanisms behind liver failure may pave the way for effective interventions.”
Research Findings
Both the Kalsotra and Diehl laboratories have extensively studied the molecular and cellular foundations of liver regeneration. Over the past five years, they discovered that liver cells must reprogram their gene expression to transition to fetal-like progenitor cells, multiply, and subsequently revert to mature functioning cells. With this knowledge, the research team explored how these regeneration mechanisms are disrupted in alcohol-associated liver disease.
The researchers analyzed liver samples, comparing healthy tissues with those affected by alcohol-associated hepatitis or cirrhosis, obtained from Johns Hopkins University Hospital through a National Institute for Alcohol Abuse and Alcoholism initiative.
They observed that damaged liver cells initiated the process of reverting to a regenerative state but did not complete it, remaining in a state of transitional limbo. “They are neither functional adult cells nor proliferative progenitor cells,” explained U. of I. graduate students Ullas Chembazhi and Sushant Bangru, co-first authors of the study. “As a result, remaining cells face increased pressure to regenerate, leading to all cells ending up in a nonproductive quasi-progenitor state; this ultimately contributes to liver failure.”
Investigating RNA Splicing Deficiencies
To determine why liver cells became entrapped in this transitional state, the research team examined the proteins produced by liver cells and, consequently, the RNA molecules that convey the instructions for those proteins from DNA. Unlike many studies that evaluate only the total amounts of RNA or protein, Kalsotra’s team employed deep RNA sequencing technology and computational analyses to focus on RNA splicing. This step is crucial for assembling different segments of genetic instructions to synthesize proteins.
“In our comparisons, we identified widespread RNA missplicing in cases of alcohol-related liver disease across thousands of genes, inhibiting major protein functions,” Kalsotra remarked. The researchers identified a potential factor contributing to RNA missplicing: alcohol-damaged liver cells exhibited a deficiency of the protein ESRP2, essential for proper RNA splicing.
“Proteins operate in specific locations within the cell, determined by sequences within the protein itself. We found that in many instances, the sequence responsible for protein localization was misspliced,” Kalsotra added. “As a result, key proteins required for effective liver regeneration were retained in the cytoplasm rather than being delivered to the nucleus, where they are needed.”
Conclusions and Future Directions
To further validate the link to ESRP2 deficiency, researchers studied mice lacking the gene responsible for producing ESRP2. These mice demonstrated liver damage and regeneration failure akin to that observed in patients with advanced alcohol-related hepatitis.
The study also examined why ESRP2 levels were reduced in liver cells from patients with alcohol-related hepatitis. The researchers discovered that liver support and immune cells, attracted to tissue damaged by excessive alcohol consumption, released high levels of inflammatory and growth factors that suppressed ESRP2 production and activity.
To corroborate these findings, the research team treated liver cell cultures with a molecule that inhibits the receptor for one of the inflammation-promoting factors. The treatment resulted in a recovery of ESRP2 levels and corrected RNA splicing activity, suggesting a potential therapeutic pathway for treatment.
“I am optimistic that these findings will serve as a foundation for future clinical studies,” Kalsotra concluded. “The identification of misspliced RNAs may lead to new diagnostic markers or treatments aimed at reducing inflammation. Correcting splicing defects could significantly enhance liver recovery and restoration.”
The research team included U. of I. biochemistry graduate students Diptatanu Das and Subhashis Natua; U. of I. undergraduate students Katelyn Toohill, Ishita Purwar, and Anuprova Bhowmik; along with researchers from Johns Hopkins University School of Medicine, Northwestern University, and Duke University School of Medicine.
This study was supported by the National Institutes of Health, the Chan Zuckerberg Biohub Chicago, the Duke Endowment, and the Muscular Dystrophy Association.
Key Health Takeaway
Understanding the disruptions in liver regeneration caused by alcohol-related factors may lead to the development of novel diagnostic and therapeutic strategies, potentially improving recovery rates for patients with alcohol-associated liver disease.
