Researchers at Spain’s National Cancer Research Centre (CNIO) have shown that the amino acid glutamate plays an important role in initiating a rapid recovery process after liver damage. The findings, published in Nature, show that glutamate, which is known for its role in nerve signaling, is produced by liver cells and released into the bloodstream after liver damage to aid tissue repair.
“Unhealthy diet and lifestyle can affect liver regeneration,” said senior author Nabil Djouder, PhD, head of the CNIO growth factors, nutrients, and cancer group. “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 tumor.”
This discovery provides a clearer understanding of how the liver, known for its ability to regenerate damaged tissue, begins this process rapidly after acute injury. It also suggests the possibility of using glutamate supplementation in patients who have undergone hepatectomy or are suffering from chronic liver diseases such as cirrhosis.
While the liver’s ability to regenerate has been broadly studied, the exact mechanisms involved have remained largely unknown. The new research shows that after liver injury, a specific population of hepatocytes produces glutamate, which in turn activates a series of biological processes leading to liver repair. After it is produced by liver cells, the glutamate travels through the bloodstream to the bone marrow, where it interacts with monocytes—immune cells that will become macrophages. These macrophages, influenced by glutamate, reprogram their metabolism and secrete growth factors that stimulate hepatocyte proliferation.
According to the CNIO researchers, the mechanism also sheds light on how the liver’s different areas coordinate their regenerative efforts. Specifically, they discovered that hepatocytes producing the protein glutamine synthetase play a key role in regulating glutamate levels during regeneration. The investigators demonstrated that when glutamine synthetase activity is inhibited, glutamate levels rise, accelerating the regenerative process. This regulation ensures that liver regeneration occurs in a controlled and efficient manner and can adapt to the body’s needs.
“These findings suggest that manipulating glutamate levels could become an important strategy for improving liver regeneration, especially in patients with chronic liver conditions like cirrhosis,” said María del Mar Rigual, first author of the study and a predoctoral researcher in the Djouder lab.
The possibility that dietary supplementation of glutamate could serve as a therapeutic tool to accelerate liver regeneration in patients with liver damage, could be applied to patients with a range of conditions including those recovering from hepatectomy, a surgery in which part of the liver is removed to treat tumors, or those awaiting liver transplants.
It could also potentially offer treatment pathways for people with cirrhosis or those suffering from acute liver injury due to poor dietary habits, alcohol consumption, or other factors that impair liver function.
The current research was conducted in animal models and also leveraged bioinformatics tools to test the results using information from human hepatocyte databases. The next step for the research is to begin clinical trials to determine the safety and dosing regimens that might be appropriate for glutamate supplementation in humans.
“The discovery of how glutamate influences liver regeneration opens up new possibilities for treating liver diseases,” said Djouder. “By understanding the molecular processes involved, we may be able to develop targeted therapies that enhance liver function and improve outcomes for patients with chronic liver conditions.”
