During recent years, the revolution of GLP-1 drugs (such as semaglutide, the active ingredient in Ozempic) has been narrated mainly through the numbers on the scale. The success of these drugs in treating obesity and type 2 diabetes … has eclipsed a phenomenon that doctors observed with bewilderment in their consultations: patients who barely lost weight but whose liver, punished by fat and inflammation, experienced amazing improvement. Until now, we assumed that the liver benefit was a side effect of losing kilos. However, a new study published in the journal ‘Cell Metabolism’ has just proven us wrong.
The research, developed at the Lunenfeld-Tanenbaum Research Institute in Toronto (Canada), reveals that semaglutide has a “direct route” to repair the liver. The finding is crucial to understanding the treatment of steatohepatitis associated with metabolic dysfunction or MASH, a severe form of fatty liver that affects a quarter of the population and can lead to cirrhosis or cancer. Scientists have identified that the drug does not require the patient to lose weight to begin cleansing the organ; It does this by activating specific receptors whose existence was unknown in the liver tissue.
The invisible cells
The doctor Daniel Druckersenior researcher at the aforementioned institute, professor at the University of Toronto and one of the key figures in the discovery of GLP-1 in the 1980s, has led this work that challenges medical dogma. “We have seen in clinical trials that patients who lose very little weight show the same reductions in liver inflammation and enzyme levels as those who lose a lot of weight. Now we know why,” explains Drucker. The enigma was that, until now, it was thought that liver cells did not have the receptor where semaglutide attaches.
To solve the puzzle, the Galician Maria Gonzalez Rellána postdoctoral researcher and key player in the study, used advanced mouse models and deep molecular analyses. Their work allowed us to identify two types of cells that do carry these receptors: the T lymphocytes of the immune system and, above all, hepatic sinusoidal endothelial cells (LSEC). The latter are only 3% of the volume of the liver, but they act as a kind of molecular “strainer” that filters substances between the blood and the organ. They are small, but their command power is immense.
Change in clinical strategy
To show that the benefit was independent of weight, the team conducted a ultimate experiment. They used mice that lacked the brain receptors that control appetite, and although these animals did not stop eating or lose weight when receiving semaglutide, their liver status improved. In contrast, in mice lacking receptors on LSEC cells, the drug had no effect on the liver, even after the animals lost 20% of their body weight by other methods. This confirms that the key is not thinness, but the activation of that specific switch in the liver.
The key is not thinness, but the activation of a specific switch in the liver
«It turns out that the receptor responsible for these benefits is in a population of cells very specialized» says Drucker. According to the researcher, these cells orchestrate the production of molecules that “talk” to the rest of the liver to calm the inflammatory environment. This discovery has immediate practical implications: doctors could prescribe lower doses of these drugs to treat liver diseases, avoiding the side effects associated with the high doses necessary for extreme weight loss and reducing treatment costs.
Drucker insists that this does not diminish the importance of the fight against obesity, but it does change the scale of therapeutic success. «We are not saying that weight loss is not important, because many things They improve when the patient loses weight. But now we know that weight should not be the only measure of success, because these medications will improve liver health whether or not the patient weighs,” concludes the expert.
