Researchers at the National Cancer Research Centre in Spain (CNIO) have discovered a mechanism that is triggered just minutes after acute liver damage occurs—and it could lead to treatments for those with severe liver problems.

The avenues for future treatments of liver damage 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,” wrote the authors in a paper published in ‘Nature’.

The liver is a vital organ, crucial to digestion, metabolism, and the elimination of toxins. It has a unique ability to regenerate, 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—and such diseases are becoming increasingly prevalent, associated with poor dietary habits or alcohol consumption. So activating liver regeneration is key to treating the disease.

Learning to activate liver regeneration is therefore a priority today, to benefit patients with liver damage and also those who’ve had part of their liver cut out to remove a tumor.

The research has discovered in animal models this 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.

“Our results describe a fundamental and universal mechanism that allows the liver to regenerate after acute damage,” explained Nabil Djouder, head of the CNIO Growth Factors, Nutrients and Cancer Group and senior author of the study.

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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, according to a CINO news release.

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 reprograms 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.”

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, organized in different areas; the hepatocytes in each area perform specific metabolic functions. The study reveals that hepatocytes producing a protein known as glutamine synthetase, which regulates glutamate levels, play a key role in regeneration.

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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 mice, but the 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.”

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The first author of the paper, CNIO researcher María del Mar Rigual also wants future research to explore using glutamate supplements in humans who have undergone liver resection for tumor removal.

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