A new study has shown that alcohol intake can interfere with the natural regenerative abilities of the liver. Alcohol can keep cells in a kind of limbo between a functional or regenerative state, even when drinking stops. This limbo is caused by inflammation that disrupts how RNA molecules are processed before proteins are produced, according to new research reported in Nature Communications. The findings could also open up new treatment options for alcohol-associated liver disease.
The liver is a unique organ that is able to partially regenerate after a portion of it is damaged or removed. But in alcohol-associated liver disease, the liver loses its unique regenerative capacity. This disorder leads to the deaths of around 3 million people every year.
“We knew that the liver stops functioning and stops regenerating in patients with alcohol-related hepatitis and cirrhosis, even when a patient has discontinued consuming alcohol, but we didn’t know why,” said co-corresponding study author Auinash Kalsotra, a professor at the University of Illinois Urbana-Champaign, among other appointments. “The only real life-saving treatment option once a patient reaches the liver failure stage in those diseases is transplantation. But if we understood why these livers were failing, maybe we could intervene.”
This research team has determined that liver cells can reprogram how genes are expressed, and can do so to revert to a progenitor state, like cells found in the fetus. These progenitor-like cells can multiply and mature again to become new, functional liver cells.
In this study, the investigators wanted to learn more about what goes awry in this process in alcohol-associated liver disease. They compared liver samples from alcohol-associated hepatitis or cirrhosis patients to liver samples from unaffected individuals.
They found that there were cells in the patient livers that had started to revert to a progenitor state, but got stuck. The researchers looked to the RNA molecules in those cells, and found that they were being incorrectly edited, or spliced in the diseased cells. This was having a negative impact on proteins.
Additional work showed that a RNA-binding protein called ESRP2, which normally helps maintain proper RNA splicing, was lacking in diseased cells. The resulting aberrant splicing was sending proteins to the wrong places in cells, and important proteins were not carrying out their functions.
These findings were also confirmed in a mouse model that lacked the ESRP2 protein. These mice developed symptoms that were similar to those seen in advanced alcohol-related hepatitis.
The scientists also discovered that immune and support cells that were moving to areas with liver damage were promoting inflammation. This inflammatory activity was suppressing ESRP2 function, leading to aberrant splicing, and cells that were unable to regenerate.
“I’m hopeful these findings will become a launching pad for future clinical studies. We can use these misspliced RNAs as diagnostic markers or develop treatments that can curb the inflammation. And if we can correct the splicing defects, then maybe we can improve recovery and restore damaged livers,” added Kalsotra.
Sources: University of Illinois at Urbana-Champaign, Nature Communications