The liver is known for its ability to regenerate. It can regrow itself completely, even after two-thirds of its mass is surgically removed. But damage from drugs, alcohol abuse, or obesity can eventually cause the liver to fail. Currently, transplantation is the only effective treatment for end-stage liver disease.
However, there is a shortage of organs available for transplantation. In the US, patients may have to wait 30 days to more than five years to receive a liver for transplant.
But what if instead of liver transplant there was a drug that could help the liver regenerate itself?
I am the founder and director of the Pittsburgh Liver Research Center and run a lab that studies liver regeneration and cancer. In our recently published study, my team and I found that activating a particular protein with a new drug can help accelerate regeneration and recovery after severe liver injury or partial surgical removal in mice.
Key players in liver regeneration
The liver performs more than 500 important functions in your body, including producing proteins that transport fat throughout the body, converting excess glucose into glycogen for storage, and breaking down toxins such as ammonia, among others.
Liver cells, or hepatocytes, take on these many tasks through a divide-and-conquer strategy known as zoning. This separates the liver into three zones with different tasks, and cells are directed to perform specialized functions by turning on specific genes that are active in each zone. However, what exactly controls the expression of these genes is poorly understood.
Over the past two decades, my team and other labs have identified one group of 19 proteins called Wnts that play an important role in controlling liver function and regeneration. While researchers know that Wnt proteins help activate the repair process in damaged liver cells, it’s been a mystery which ones actually control zoning and regeneration, as well as their exact location in the liver.
To identify these proteins and where they came from, my team and I used a new technology called molecular cartography to determine how strong and where 100 liver function genes are active. We found that only two of the 19 Wnt genes, Wnt2 and Wnt9b, were functionally present in the liver. We also found that Wnt2 and Wnt9b were located in the endothelial cells lining blood vessels in zone 3 of the liver, an area involved in a number of metabolic functions.
To our surprise, eliminating these two Wnt genes resulted in all liver cells only expressing genes typically restricted to zone 1, significantly limiting the overall function of the liver. This finding suggests that liver cells experience a continued push and pull in gene activation that can alter their functions, and Wnt is the master regulator of this process.
Eliminating the two Wnt genes from endothelial cells also stopped the liver cells from dividing, and thus regeneration, after partial surgical removal of the liver.
Liver Regeneration After Tylenol Overdose
We then decided to test whether a new drug could help restore liver zoning and regeneration. This drug, an antibody called FL6.13, shares similar functions with Wnt proteins, including activating liver regeneration.
Over the course of two days, we gave this drug to mice that had been genetically engineered to lack Wnt2 and Wnt9b in their liver endothelial cells. We found that the drug was able to almost completely restore the cell division and repair functions of the liver.
Finally, we wanted to test how well this drug worked to restore the liver after a Tylenol overdose. Tylenol, or acetaminophen, is an over-the-counter medication commonly used to treat fever and pain. However, an overdose of Tylenol can cause serious liver damage. Without immediate medical attention, it can lead to liver failure and death. Tylenol poisoning is one of the most common causes of severe liver damage requiring liver transplantation in the US. Despite this, there is currently only one drug available to treat it, and it can only prevent liver damage if taken shortly after an overdose.
We tested our new drug on mice with liver damage from toxic doses of Tylenol. We found that one dose was able to reduce liver damage biomarkers – proteins that the liver releases when injured – in the blood and reduce the death of liver tissue. These findings indicate that liver cell repair and tissue regeneration take place.
Reducing the Need for Transplant
One way to address liver transplant shortages is to improve treatments for liver disease. While current drugs can effectively cure hepatitis C, a viral infection that causes inflammation of the liver, other liver diseases have not made the same progress. Because there are very few effective treatments available for diseases such as non-alcoholic fatty liver disease and alcoholic liver disease, many patients worsen and eventually require a liver transplant.
My team and I believe that improving the liver’s ability to repair itself could help avoid the need for transplantation. Further study of drugs that promote liver regeneration may help reduce the burden of liver disease worldwide.
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