The liver is known for its ability to regenerate. He can completely regenerate even after two-thirds of his mass has been surgically removed. But damage from medications, alcohol abuse, or obesity can eventually lead to liver failure.
Currently, the only effective treatment for end-stage liver disease is transplantation.
However, there is a shortage of available organs for transplantation. Patients may have to wait from 30 days to more than 5 years receive a liver for a transplant in the United States. Of the more than 11,600 patients on the waiting list to receive a liver transplant in 2021, just over 9,200 received one.
What if, instead of a liver transplant, there was a drug that could help the liver regenerate?
I am the founding director of Pittsburgh Liver Research Center and run a lab study liver regeneration and cancer. In our recently published researchmy team and I found that activating a particular protein with a new drug can help accelerate regeneration and repair after severe liver injury or partial surgical removal in mice.
Key players in liver regeneration
The liver performs more than 500 key functions in your body, including produce proteins that transport fat around the body, convert excess glucose into glycogen for storage, and break down toxins like ammonia, among others.
Liver cells, or hepatocytes, take on these many tasks through a divide-and-conquer strategy, also called zoning. This separates the liver into three areas with different tasks, and the cells are directed to perform specialized functions by activating specific genes active in each area.
However, what exactly controls the expression of these genes has been poorly understood.
Over the past two decades, my team and other labs have identified a group of 19 proteins called wnts which play an important role in controlling the function and regeneration of the liver.
While researchers know that Wnt proteins help activate the repair process in damaged liver cells, which cells actually control zonation and regeneration, as well as their exact location in the liver, remains a mystery.
To identify these proteins and their origin, my team and I used a new technology called molecular mapping to identify how and where 100 liver function genes are active.
We found that only two of 19 Wnt genes, Wnt2 and Wnt9b, were functionally present in the liver. We also found that Wnt2 and Wnt9b were located in endothelial cells lining blood vessels in zone 3 of the liver, an area that plays a role in a number of metabolic functions.
To our surprise, the elimination of these two Wnt genes resulted in all liver cells expressing only genes typically restricted to zone 1, severely limiting overall liver function.
This finding suggests that liver cells undergo a continuous push and pull in the activation of genes that can alter their functions, and Wnt is the master regulator of this process.
Removal of the two Wnt genes from endothelial cells also completely halted liver cell division, and therefore regeneration, after partial liver removal surgery.
Liver regeneration after an overdose of Tylenol
We then decided to test whether a new drug could help recover liver zoning and regeneration. This drug, a antibody called FL6.13, shares similar functions with Wnt proteins, including the activation of liver regeneration.
Over the course of two days, we gave this drug to mice that were genetically engineered to lack Wnt2 and Wnt9b in their liver endothelial cells. We found that the drug was able to almost completely recover liver cell division and repair functions.
Finally, we wanted to test the effectiveness of this drug in repairing the liver after an overdose of Tylenol. Tylenol, or acetaminophen, is an over-the-counter medication commonly used to treat fever and pain.
However, an overdose of Tylenol can cause severe 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 United States.
Despite this, there is currently only one drug available to treat it, and it can only prevent liver damage if taken soon after an overdose.
We tested our new drug on mice with liver damage caused by toxic doses of Tylenol. We found that one dose was able to decrease liver injury biomarkers – the proteins the liver releases when injured – in the blood and reduce liver tissue death.
These results indicate that liver cell repair and tissue regeneration are occurring.
Reduce the need for a transplant
One way to address liver transplant shortages is to improve treatments for liver disease. While current drugs can effectively cure Hepatitis Ca viral infection that causes inflammation of the liver, other liver diseases have not seen the same progress.
Because very few effective treatments are available for conditions such as non-alcoholic fatty liver disease and alcoholic liver disease, many patients get worse and end up needing liver transplants.
My team and I believe that improving the liver’s ability to repair itself could help circumvent the need for transplantation. Further study of drugs that promote liver regeneration could help reduce the burden of liver disease worldwide.