Researchers have discovered a new mechanism for rapid liver regeneration triggered by glutamate

(Press-News.org) Research conducted by the National Cancer Research Centre (CNIO), published today in ‘Nature’, reveals a mechanism in mice that is triggered just minutes after acute liver damage occurs. This finding opens up avenues for future treatments of serious liver damage to include a diet enriched with the amino acid glutamate. Glutamate supplementation can promote liver regeneration and benefit patients in recovery following hepatectomy or awaiting a transplant, the authors write in ‘Nature’. Activating liver regeneration is key to treating diseases that involve severe liver damage, which are becoming increasingly frequent and are associated with poor dietary habits and alcohol consumption. The liver is a vital organ, crucial to digestion, metabolism and the elimination of toxins. It has a unique ability, regeneration, which allows it to replace liver cells damaged by the very toxins that these cells eliminate. However, the liver stops regenerating in cases of diseases that involve chronic liver damage –such as cirrhosis–. Such diseases are becoming increasingly prevalent, associated with bad dietary habits and alcohol.

Learning to activate liver regeneration is therefore a priority today, to benefit mainly patients with severe liver damage and also those who have had part of their liver cut out to remove a tumour.

Research at the National Cancer Research Centre (CNIO), published today in Nature, has discovered in animal models a previously unknown mechanism of liver regeneration. It is a process that is triggered very quickly, just a few minutes after acute liver damage occurs, with the amino acid glutamate playing a key role.

The authors write in Nature that, in light of their results, nutritional glutamate supplementation can effectively promote liver regeneration and benefit patients with severe and chronic liver damage, such as those recovering after hepatectomy, to stimulate liver growth, or even those awaiting a transplant.

As explained by Nabil Djouder, head of the CNIO Growth Factors, Nutrients and Cancer Group and senior author of the study, “unhealthy diet and lifestyle can affect liver regeneration. Our results describe a fundamental and universal mechanism that allows the liver to regenerate after acute damage. These results may also help improve liver regenerative capacity in patients with severe liver damage, such as cirrhosis, or those who have undergone partial resection in surgery to remove a tumour.”

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

A “complex and ingenious” perspective on liver regeneration

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 very novel, as it describes communication between two different organs, the liver and bone marrow, involving the immune system.

The results show that liver and bone marrow are interconnected by glutamate. After acute liver damage, liver cells, called hepatocytes, produce glutamate and send it into the bloodstream; through the blood, glutamate reaches the bone marrow, inside the bones, where it activates monocytes, a type of immune system cell. Monocytes then travel to the liver and along the way become macrophages – also immune cells. The presence of glutamate reprogrammes the metabolism of macrophages, and these consequently begin to secrete a growth factor that leads to an increase in hepatocyte production.

In other words, a rapid chain of events allows glutamate to trigger liver regeneration in just minutes, through changes in the macrophage metabolism. It is, says Djouder, “a new, complex and ingenious perspective on how the liver stimulates its own regeneration.”

A specific population of hepatocytes produces glutamate

The research also clarifies a previously unanswered question: how the various areas of the liver are coordinated during regeneration. In the liver, there are different types of hepatocytes, organised in different areas; the hepatocytes in each area perform specific metabolic functions. The study now published in Nature reveals that hepatocytes producing a protein known as glutamine synthetase, which regulates glutamate levels, play a key role in regeneration.

According to the CNIO group, when glutamine synthetase is inhibited, there is more glutamate in circulation, which accelerates liver regeneration. This is what happens when the liver suffers acute damage: glutamine synthase activity decreases, blood glutamate increases, and from there, the connection with the bone marrow is established, reprogramming macrophages and stimulating hepatocyte proliferation.

Possible therapeutic applications

The experiments have been carried out in animal models, but their results have been tested with bioinformatics tools, using databases of mouse and human hepatocytes.

According to Djouder, “dietary glutamate supplementation may simply be recommended in the future after liver extirpation, and also to reduce liver damage caused by cirrhosis, which is common in patients with poor diet or unhealthy lifestyle or other serious liver diseases.”

Rigual also suggests adding another goal for future research: “Exploring further the possibility of using glutamate supplements in humans who have undergone liver resection for tumour removal.”

Funding

This study has been financed with state public funds from the Spanish Department of Science, Innovation and Universities through the ‘Research Challenges’ programme, and private funds from Fundación BBVA and the Spanish Cancer Association (AECC).

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