Study Unveils Why Liver Can’t Heal After Long-Term Alcohol Use

The liver is truly remarkable; it can regenerate even after injury or damage. However, there are limits to its healing abilities. Prolonged alcohol consumption can hinder its self-repair capabilities, even when someone stops drinking. A recent study has shed light on the reasons behind this, delving deep into the molecular mechanisms involved.

“We were aware that the liver ceases to regenerate in cases of alcohol-related hepatitis and cirrhosis, even after alcohol consumption has halted, but the reasons were unclear,” explained Auinash Kalsotra, a biochemistry professor at the University of Illinois.

“Transplantation is often the only viable treatment option at the stage of liver failure in these conditions. Understanding why liver failure occurs could pave the way for potential interventions.”

To explore the issue, Kalsotra and his team, alongside Duke University hepatologist Professor Anna Mae Diehl, compared liver samples from healthy individuals with those suffering from alcohol-related hepatitis and cirrhosis.

They found that in diseased livers, damaged cells were stuck in a sort of limbo. Instead of transitioning into a regenerating state, the cells remained caught between being damaged and healing.

In normal livers, cells that require regeneration revert to a type of progenitor cell that can grow and eventually transform back into functional adult cells. The alcoholic liver cells, however, were trapped at the beginning of this cycle.

“These cells are neither fully functional nor capable of proliferation. As a result, stress mounts on the remaining healthy cells, which attempt to regenerate but end up in this ineffective quasi-progenitor state. This is ultimately what leads to liver failure,” noted graduate students Ullas Chembazhi and Sushant Bangru, who co-authored the study.

The researchers sought to understand the underlying causes of this phenomenon by analyzing the differences in gene expression between healthy and affected liver samples on a molecular level. This involved examining RNA and proteins, focusing on how changes in gene expression profile influenced the regenerative process.

Gene expression starts with DNA being transcribed into messenger RNAs (mRNAs), which carry instructions to produce proteins at ribosomes. Before proteins are made, some sections of the mRNAs are removed in a process called splicing.

Kalsotra and Diehl’s research team discovered that splicing was disrupted in diseased cells, causing proteins encoded by the mRNA to end up in the wrong locations, thus hampering regeneration.

“Proteins operate in specific areas of the cell, and their location is directed by sequences within them. We found that in many cases, the sequences responsible for protein localization were incorrectly spliced, which is why thorough analysis was crucial,” Kalsotra elaborated.

“While the quantity of RNA and protein remained consistent, the proteins were misdirected. Due to splicing errors, essential proteins necessary for liver regeneration became trapped in the cytoplasm instead of reaching the nucleus as they should.”

The team identified that this splicing issue was driven by a shortage of a protein critical for binding to mRNA during splicing. This deficiency was linked to inflammation caused by alcohol-related liver diseases. On a brighter note, this new insight could lead to innovative treatments.

“I’m optimistic that these findings could serve as a foundation for future clinical studies. We might utilize these incorrectly spliced RNAs as diagnostic markers, or develop treatments to reduce inflammation. If we can fix the splicing errors, perhaps we could enhance recovery and heal damaged livers,” Kalsotra concluded.

The study appears in Nature Communications.