The liver's capacity for regeneration is well established. Even after having two-thirds of its bulk surgically removed, it can fully regenerate. The liver can, however, eventually become damaged due to pharmaceutical side effects, alcohol addiction, or obesity.
Currently, liver transplantation is the only viable treatment
for end-stage liver disease.
There aren't many organs available for transplantation, though. In the US, patients may have to wait anywhere from 30 days and more than 5 years to acquire a liver for transplant. Only a little over 9,200 of the roughly 11,600 people who were eligible for liver transplants in 2021 actually received one.
But what if there was a medication that
could aid the liver in self-regeneration rather than a liver transplant?
The Pittsburgh Liver Research Center's first director, I head a lab that looks at cancer and liver regeneration. My group and I discovered in our recently published research that in mice with severe liver damage or partial surgical excision, activating a specific protein using a novel medicine can aid in speeding up regeneration and repair.
Important participants in liver regrowth
Over 500 essential bodily processes are carried out by the liver, including the production of proteins that transport fat, the conversion of extra glucose into glycogen for storage, and the breakdown of poisons like ammonia.
Hepatocytes, or liver cells, use a divide-and-conquer tactic, also known as zonation, to accomplish these several duties. This divides the liver into three functional zones, and cells are instructed to carry out specialized activities by turning on particular genes present in each zone.
However, little is known about precisely how these genes are expressed.
My laboratory and other labs have discovered a collection of 19 proteins called Wants over the past 20 years that are crucial in regulating liver function and regeneration.
While it is known that Want proteins assist in triggering the repair process in injured liver cells, it is unknown which Want proteins truly regulate zonation and regeneration as well as their precise location in the liver.
My group and I used a new technique called molecular mapping to determine the locations and levels of activity of 100 liver function genes in order to identify these proteins and where they originated.
Only two of the 19 Want genes, Wnt2 and Wnt9b, were discovered to operate in the liver. We also discovered that Wnt2 and Wnt9b were present in zone 3 of the liver, which is involved in a lot of metabolic processes, in the endothelial cells lining the blood arteries.
Surprisingly, knocking off these two Want genes caused all liver cells to express just genes generally seen in zone 1, severely restricting the liver's ability to operate as a whole.
This finding implies that Want is the primary regulator of a continuous push and pull in gene activation that can change the functioning of liver cells.
After partial surgical ablation of the liver, regeneration was totally halted by eliminating the two Wnt genes from endothelial cells.
Liver regrowth
with a Tylenol overdose
We therefore made the decision to see if a novel medication could assist in restoring liver zonation and regeneration. Similar to want proteins, this medication, an antibody known as FL6.13, activates liver regeneration.
We administered this medication over a period of two days to mice deficient in Wnt2 and Wnt9b in the liver endothelial cells. We discovered that the medication could almost entirely restore the liver's ability to divide and mend cells.
Last but not least, we wanted to see how successfully this medication repaired the liver following a Tylenol overdose. The over-the-counter drug Tylenol, often known as acetaminophen, is frequently used to relieve fever and pain.
Tylenol overdose, however, can seriously harm the liver. If not treated right away, it can cause liver failure and even death. In the US, tylenol poisoning is one of the most frequent causes of serious liver damage necessitating a liver transplant.
Despite this, there is only one medicine that can currently be used to treat it, and even then, it can only stop liver damage if it is administered quickly after an overdose.
On mice whose livers had been damaged by toxic doses of Tylenol, we tried our novel medication. We discovered that one dose was capable of reducing blood levels of liver injury biomarkers—proteins the liver releases when injured—and liver tissue death.
These results suggest that tissue and liver cell regeneration are taking place.
Decrease in the necessity for transplants
The need for more liver transplants can be met by increasing the effectiveness of liver disease therapies. While hepatitis C, a viral infection that causes liver inflammation, can be successfully treated with modern drugs, other liver illnesses haven't made as much progress.
For conditions like nonalcoholic fatty liver disease and alcoholic liver disease, there are very few effective treatments available, which causes many patients to deteriorate and ultimately require a liver transplant.
