The Lipids & Liver research group of the UPV/EHU-University of the Basque Country has shown that, by silencing the Mat1a gene, the specific modification of methionine use in the livers of obese mice has a global effect on the body, because obesity is prevented and reversed, insulin resistance and circulating excess of lipids disappear and liver lipids are used up. The study has been published by Nature Communications
Obesity is a major public health problem with a growing prevalence worldwide. It is estimated that 50-60% of the population will be obese by 2030. Obesity is an established risk factor for various diseases, such as non-alcoholic fatty liver disease, now also known as metabolic hepatic steatosis, type 2 diabetes and dyslipidaemia (alteration of blood lipid and protein levels). Weight loss through pharmacological treatments, lifestyle interventions or even surgery are effective in treating obesity-related co-morbidities. However, when it comes to proposing new therapies, a better understanding of the connection between the various obesity-related metabolic disorders is still needed.
The lead researcher in the UPV/EHU’s Lipids & Liver group Patricia Aspichueta is delighted with the results of the research that has recently appeared in Nature Communications and which are "significant and very clear indeed". After five years of extensive collaborative research, this group provides "information on how the liver can regulate obesity and obesity-related diseases; how by modulating or restricting the use of methionine (an essential protein-generating amino acid obtained only through the diet) within the liver, we can improve body status: by improving obesity and obesity-related diseases. We have provided significant, encouraging data along this path. However, not everything has been discovered and much more needs to be provided," said the researcher.
In the collaborative study led by Dr Aspichueta, they have managed to prevent and reverse obesity as well as the associated insulin resistance and hepatosteatosis (accumulation of fat in the liver) in obese mice by increasing energy expenditure, as well as by reducing serum and liver lipids. As the doctor explained, "by specifically modifying the use of methionine in the liver through the silencing of the Mat1a gene, we obtained an overall effect on the body: the liver generates a molecule that is secreted into the bloodstream and has effects on other tissues due to its high capacity to modulate the metabolism of the whole body. Among others, one of the tissue types it regulates is brown fat; when this brown fat is activated, the body's consumption of fat in this tissue is activated, leading to a series of beneficial effects: the mice lose weight, insulin resistance disappears, excess circulating lipids in the blood disappear and liver lipids decrease”.
However, Dr Aspichueta warned that this is no more than another step. "We have conducted an analysis in animal models, but there is still a lot of work to be done: research on possible adverse effects needs to be done before we can take this to a clinical trial. Methionine can be restricted in the liver, but it should never be inhibited. This restriction leads to a number of changes on the level of liver metabolism, and care must be taken. You have to keep everything in balance, because if you keep an inhibition going for too long, it can also have a detrimental effect. Obesity is a very complex disease, involving not only the liver or adipose tissue, but also the brain. "It is such a complex disease that it has compensatory mechanisms. This research is therefore just one more drop in the ocean; important information to understand how the whole metabolism functions in this complex disease," she said.
The prevalence of obesity, being overweight, is on the rise. Between 70-80 % of patients with obesity have problems with metabolic hepatic steatosis, i.e. liver disease. In some of these patients, it progresses, leads to complications and ends up with fatty hepatitis or even liver cancer. "Our goal is to be able to determine how to halt the onset of this disease in the liver and its progression. And if we can somehow halt or reverse this obesity and all these harmful effects, we may be able to contribute to reducing the prevalence of cancer. If we can understand how to modulate this obesity and, as a result, all the associated diseases, we can slow down the progression towards this highly prevalent problem," she concluded.
In addition to the UPV/EHU’s Lipids & Liver group and the Biocruces Bizkaia Health Research Institute, researchers from the University of Santiago de Compostela- CIMUS, the CNIC, CIC bioGUNE, the Biodonostia Health Research Institute and MUSC, South Carolina (USA), as well as the company IONIS pharmaceuticals located in California, have participated in the study. In addition, the group has had the collaboration of the CIBEREHD group (CIBER National Institute for the Study of Liver and Gastrointestinal Diseases) to which it belongs.
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