• metabolismo
• oncología
• hígado

• hígado
• Aminoácidos
• Metionina

Having shown that diet can influence gene expression, science is starting to find out more about how this happens. According to an article recently published in Food and Chemical Toxicology, a diet supplemented with or deficient in methionine, an essential amino acid abundant in eggs, meat and seafood, affects the expression of genes associated with liver cell fat metabolism and genes that modify chromatin, the coiled fibers made up of DNA and proteins that form chromosomes in cells. 

The study investigated how methionine influences DNA methylation, a biochemical process involving addition of a methyl radical to the DNA molecule. This is an epigenetic change, meaning an alteration in the expression profile of the genes that define an individual's characteristics (phenotype). Epigenetic changes can be repeated in cell division and be transmitted to descendants, although they are not the same as alterations in the DNA sequence (genotype). The links between methylation and disease are widely studied by scientists at present.

To investigate the epigenetic mechanisms involved in alterations to liver cells, the researchers fed mice a methionine-deficient or methionine-supplemented diet and then extracted cells from their livers for molecular analysis. 

This study, the fourth published by the Nutrigenomics Research Group at the University of São Paulo's Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in Brazil, is based on data generated during the Ph.D. research of Alexandre Ferro Aissa, who was supported by FAPESP via a doctoral scholarship and a scholarship for a research internship abroad. 

The study also involved collaboration with a team led by Igor Pogribny, a researcher at the National Center for Toxicological Research, a branch of the United States Food and Drug Administration (FDA). Pogribny has pioneered research on methylation and the role of methionine, focusing on hepatic steatosis (non-alcoholic fatty liver disease), currently considered an epidemic. Pogribny himself suggested Aissa investigate the action of methionine on liver cells. 

Previous studies by the FCFRP-USP group, such as one reported in 2014 in Molecular Nutrition & Food Research, showed that dietary methionine deficiency and supplementation can cause molecular abnormalities associated with hepatic steatosis, including altered gene expression leading to lipid accumulation in the liver. The researchers found there that fat accumulated in liver cells only when there was a deficiency of methionine, bringing about a predisposition to cirrhosis, cancer, and other diseases. "But we didn't yet know how this happens," Aissa told Agência FAPESP. 

The findings contribute to a better understanding of the action of compounds present in diet on gene regulation, including the impact of diet on microRNAs (or miRNAs, small RNA molecules that do not give rise to proteins but regulate the functioning of genes). 

"We observed that diets with inadequate levels of methionine, especially those deficient in the amino acid, can cause dysregulation of several microRNAs that play a significant role in liver homeostasis," said Lusânia Maria Greggi Antunes, corresponding author of the article and coordinator of the Nutrigenomics Group at FCFRP-USP. "Our analyses detected a large number of genes that could be targeted by these microRNAs linked to liver homeostasis, including miR-190b-5p, miR-130b-3p, miR-376c-3p, miR-411-5p, miR-29c-3p, miR-295-3p, and miR-467d-5p, with methionine-deficient diet having the more substantial effect," Aissa said.

For Antunes, "The specific contribution of this study is a list of some of the biomarkers associated with a tissue alteration, such as the genes with an altered methylation pattern and the microRNAs linked to this process. All this can be used to improve diagnosis and prognosis."  

The group still has a large amount of data to analyze. The latest study, for example, involved female mice in their reproductive period, so that it will be possible to analyze the effects of methionine deficiency and supplementation on their descendants. They also have data on methionine metabolism and its influence on the development of cardiac disease, including epigenetic mechanisms.

• Inflamación
• Ácido mesacónico
• Ácido Itacónico
• Succinato deshidrogenasa

Research team discovers body's own anti-inflammatory substance

by Janos Krüger, Technische Universität Braunschweig

A team of scientists led by Professor Karsten Hiller from the Braunschweig Center for Systems Biology BRICS has discovered an endogenous, anti-inflammatory substance: mesaconic acid. This molecule could be a drug candidate that can be further developed to treat shock resulting from blood poisoning and autoimmune diseases such as psoriasis and inflammatory bowel disease (IBD)—without the known side effects of anti-inflammatory drugs currently in use.

Karsten Hiller's team has been working for many years on metabolic products that play a role in human immune defense. In 2013, the scientists discovered that immune cells in the blood and brain of mammals produce itaconic acid—a substance that had previously only been found in the metabolism of fungi. Itaconic acid is a natural antibiotic, so it fights bacteria but also inhibits inflammation.

As a result of this discovery, itaconic acid was the subject of numerous investigations. The researchers discovered that another metabolic product always occurs together with itaconic acid: mesaconic acid. Mesaconic acid is a chemical compound that the body produces from previously discovered itaconic acid. "We were interested in whether mesaconic acid also has an influence on inflammatory reactions," says Professor Hiller. In experiments with laboratory mice, the research team realized that this is indeed the case: if you administer mesaconic acid to mice whose immune system is currently "overshooting," i.e., showing too strong a defense reaction, the mice quickly get better. Their chance of survival increases.

When scientists find such an effect, they need to understand the metabolic processes behind it. The research consortium, which includes nine research groups from Braunschweig, Bonn, Luxembourg, La Jolla (U.S.) and Arhus (Denmark), found that mesaconic acid has a similar anti-inflammatory effect as itaconic acid. "However, there is a significant difference," says Dr. Wei He, a member of Hiller's team and first author of the Nature Metabolism study: "Unlike itaconic acid, mesaconic acid does not block the enzyme succinate dehydrogenase. This enzyme has a central role in cell metabolism."

Succinate dehydrogenase (SDH) is part of the respiratory chain. If it is inhibited—for example by itaconic acid—this has strong negative effects on metabolism. Since mesaconic acid has no blocking effect on the SDH enzyme, but a similar good anti-inflammatory effect as itaconic acid, it is particularly interesting as a potential agent against autoimmune diseases. "We now need to investigate why mesaconic acid has a positive anti-inflammatory effect on the immune system," says He.

When the researchers have precise answers to this question, concrete pharmacological investigations can begin with mesaconic acid. "Mesaconic acid could be considered as an active agent against diseases in which the immune system is too strongly activated—in septic shock and especially also autoimmune diseases such as psoriasis or inflammatory bowel disease," says Professor Hiller. "Possibly with fewer side effects than other drugs. This is because it is a substance that the body produces itself and does not affect central metabolic pathways in the cells."

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Explore further

Itaconic acid synthesis reduces interferon responses and inflammation in influenza A virus infection

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More information: Wei He et al, Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages, Nature Metabolism (2022). DOI: 10.1038/s42255-022-00565-1

Journal information: Nature Metabolism 

• Grasa parda
• Inosina