Mouse Study Reveals How to Help Speed Up The Liver’s Self-Regeneration Process : ScienceAlert

The liver is known for its ability to regenerate. It can fully regrow on its own even after two-thirds of its mass has been surgically removed. But damage from medication, alcohol abuse, or obesity can eventually cause the liver to fail.

Currently, the only effective treatment for end-stage liver disease is transplantation.

However, there is a shortage of organs available for transplantation. Patients may have to wait anywhere from 30 days to over 5 years to receive a liver for transplant in the US. Of the more than 11,600 patients on the waiting list for a liver transplant in 2021, just over 9,200 received one.

But what if instead of a liver transplant, there was a drug that could help the liver regenerate itself?

I am the founding director of the Pittsburgh Liver Research Center and direct a laboratory that studies liver regeneration and cancer. In our recently published research, my team and I found that activating a specific 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 over 500 key functions in your body, including producing proteins that move fat around the body, converting excess glucose into glycogen for storage, and breaking down toxins like ammonia.

Liver cells, or hepatocytes, perform these many roles through a divide-and-conquer strategy known as zoning. This divides the liver into three zones with different tasks, and directs the cells to perform specialized functions by activating specific genes 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 a group of 19 proteins called Wnts that play important roles in controlling liver function and regeneration.

While researchers know that Wnt proteins help activate the repair process in damaged liver cells, which ones actually control zonation and regeneration, as well as their precise location in the liver, has been a mystery.

To identify these proteins and their origins, my team and I used a new technology called molecular mapping to determine how strongly and where 100 liver function genes are active.

We found that only two of 19 Wnt genes, Wnt2 and Wnt9b, were functional in the liver. We also found that Wnt2 and Wnt9b reside in the endothelial cells lining the blood vessels in zone 3 of the liver, an area involved 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 experience an ongoing push-and-pull of gene activation that can alter their functions, and Wnt is the key regulator of this process.

Elimination of the two Wnt genes from endothelial cells also completely stopped liver cell division 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 zonation and regeneration. This drug, an antibody called FL6.13, has functions similar to 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 division and repair functions of the liver cells.

Finally, we wanted to test how well this drug works in repairing 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 severe liver damage. Without prompt medical attention, it can lead to liver failure and death. Tylenol poisoning is one of the most common causes of severe liver damage requiring a liver transplant 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 shortly after an overdose.

We tested our new drug on mice with liver damage from toxic doses of Tylenol. We found that one dose could reduce liver injury biomarkers – proteins that the liver releases when injured – in the blood and reduce liver tissue death.

These findings indicate that liver cell repair and tissue regeneration are occurring.

Reducing the need for a transplant

One way to address the shortage of liver transplants is to improve the treatment of liver disease. While current drugs can effectively cure hepatitis C, a viral infection that causes liver inflammation, other liver diseases have not made the same advances.

With very few effective treatments available for diseases such as nonalcoholic fatty liver disease and alcoholic liver disease, many patients deteriorate and eventually require liver transplantation.

My team and I believe that improving the liver’s ability to repair itself could help obviate the need for a transplant. Further studies on drugs that promote liver regeneration could help reduce the burden of liver disease worldwide.

Satdarshan Monga, Professor of Pathology and Medicine, University of Pittsburgh Health Sciences

This article was republished by The Conversation under a Creative Commons license. Read the original article.