The liver is one of the most amazing organs in the human body. It has the power to repair itself even after being badly hurt.
But for people who drink too much alcohol, this ability to heal can break down—and stay broken even after they stop drinking.
A new study by scientists from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago reveals why this happens.
Every year, about 3 million people die from alcohol-related liver disease around the world. This disease includes severe liver damage like hepatitis and cirrhosis.
Once the liver reaches the point of failure, the only way to save a patient is through a liver transplant. But researchers wanted to know why the liver stops healing itself in the first place and if it’s possible to fix the problem earlier.
The liver normally heals by transforming its cells. After injury, liver cells can change into a more basic, baby-like state. These special cells multiply and later grow back into healthy adult liver cells. This process has been observed in past research, but scientists didn’t know why it stopped working in people with alcohol-related liver disease.
In the new study, researchers compared healthy liver samples to samples from people with alcohol-related hepatitis or cirrhosis. The first thing they noticed was that liver cells in sick people tried to start the healing process, but then got stuck halfway.
These cells didn’t fully turn into healing cells, nor did they go back to being normal working liver cells. They were caught in the middle, in a state that couldn’t help the liver recover.
Because these stuck cells couldn’t do their jobs, the rest of the liver had to work harder. But even those remaining healthy cells began to break down under pressure and also got stuck. This led to liver failure.
To understand what caused the cells to get stuck, the scientists looked closely at the proteins the liver was making, and the RNA—the messenger that tells cells how to build proteins. They found that in diseased livers, thousands of RNA messages were being miswritten, or “misspliced,” meaning they weren’t put together the right way. This made the proteins malfunction.
One protein called ESRP2 stood out. It normally helps RNA get stitched together correctly. But in damaged livers, ESRP2 levels were too low. Without it, the instructions for proteins were jumbled, and even when the liver made proteins, they often ended up in the wrong place in the cell and couldn’t do their job.
The team tested their theory in mice by turning off the gene that makes ESRP2. The mice showed the same liver damage and failed healing seen in human patients. But why was ESRP2 missing in the first place?
It turns out that when the liver gets hurt by alcohol, other cells in the body rush in to help. These cells release inflammation chemicals. Unfortunately, those same chemicals stop ESRP2 from being made.
The researchers then tried blocking one of the inflammation signals in lab-grown liver cells. When they did this, ESRP2 came back and RNA splicing returned to normal. This suggests that stopping certain inflammation signals could help the liver heal again.
This research gives hope that one day, doctors might be able to help damaged livers heal themselves again without needing a transplant. If scientists can find a way to fix the RNA splicing or reduce harmful inflammation, more people could survive alcohol-related liver disease.
This study also shows that it’s not just about how much RNA or protein a cell has. It’s also about whether the proteins are built and placed correctly to do their jobs.
In summary, the study reveals a hidden problem in alcohol-related liver disease: a failure in how cells make and use proteins, caused by both inflammation and a loss of an important helper protein, ESRP2. These discoveries could lead to better ways to diagnose and treat people before their liver damage becomes life-threatening.
The study is published in Nature Communications.
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