Glutamate key to unlock liver regeneration after acute damage

The liver is a vital organ, crucial for digestion, metabolism and elimination of toxins. It has a unique capacity, regeneration, which allows it to replace liver cells that have been damaged by the same toxins that eliminate these cells. However, the liver stops being regenerated in cases of diseases that include chronic liver damage – such as cirrhosis -. Such diseases become increasingly widespread, associated with poor eating habits and alcohol.

Learning the activation of liver regeneration is therefore a priority today, to benefit mainly patients with severe liver damage and also those who had part of their liver cut to remove a tumor.

Research at the National Cancer Research Center (CNIO), published today in NatureHe has discovered in animal models a previously unknown liver regeneration mechanism. This is a process that is activated very quickly, just minutes after acute liver damage, with the glutamic amino acid playing a key role.

The authors write Nature That, in the light of their effects, nutritional supplementation of glutamate can effectively promote liver regeneration and benefit patients with severe and chronic liver damage, such as those who recover after hepatectomy, to stimulate the growth of the liver or even those

As explained by Nabil Djouder, head of CNIO growth factors, nutrients and the cancer group and the top author of the study, “unhealthy diet and lifestyle can affect liver regeneration. Surgery to remove a tumor. ”

The first author of the document is CNIO María del Mar Rigual researcher.

A “complex and smart” perspective for the regeneration of the liver

Liver regeneration was known to occur through the proliferation of liver cells, known as hepatocytes. However, the molecular mechanisms involved were not fully understood. This current discovery is a very novel, as it describes the communication between two different organs, the liver and bone marrow, which includes the immune system.

The results show that the liver and bone marrow are interconnected with glutamate. After acute liver damage, the liver cells, called hepatocytes, produce glutamate and send it to the bloodstream. Through the blood, the glutamate reaches the bone marrow, in the bones, where it activates the monocytes, a type of immune system. The monocytes then travel to the liver and along the road become macrophages – also immune cells. The presence of glutamate reschedule the metabolism of macrophages and they begin to secrete a growth factor that leads to an increase in hepatocyte production.

In other words, a rapid event chain allows glutamic to activate liver regeneration in a few minutes, through changes in macrophages metabolism. It is, says Djouder, “a new, complex and smart perspective on how the liver stimulates its own regeneration.”

A particular population of hepatocytes produces glutamate

The research also clarifies a previous unanswered question: How the various areas of the liver coordinate during the Renaissance. In the liver, there are different types of hepatocytes, organized in different areas. Hepatocytes in each area perform specific metabolic functions. The study now was published in Nature It reveals that hepatocytes that produce a protein known as glutamine synthesis, which regulates glutamine levels, play a key role in regeneration.

According to the CNIO group, when glutamine synthesis is suspended, there is more glutamine circulation, which accelerates liver regeneration. This happens when the liver suffers from acute damage: Glutamine synthesis activity is reduced, glutamic blood increases and from there, bone marrow connection is created, rescheduled macrophages and stimulating hepatocyte proliferation.

Possible therapeutic applications

The experiments were conducted on animal models, but their effects have been tested with bioinformatics tools, using mice and human hepatocyte databases.

Completing the dietary glutamate may simply be recommended in the future after the spread of the liver and also reduce the liver damage caused by cirrhosis, which is common to patients with poor nutrition or unhealthy lifestyle or other serious liver diseases. “

Nabil Djouder, Head of CNIO Development Factors, Nutrients and Cancer Group and Senior Author of the Study

Rigual also proposes the addition of another goal for future research: “further exploring the possibility of using glutamate supplements to people who have undergone liver resection to remove the tumor.”