Imagine two patients with liver disease. Both are taking semaglutide, yet one loses a significant amount of weight while the other barely loses any. Surprisingly, their livers improve in a similar way. Until now, no one knew exactly why that was happening.
Researchers at Toronto’s Sinai Health have now solved that mystery. They found that semaglutide, the active ingredient in popular weight‑loss drugs, does not help the liver only indirectly through weight reduction. According to their findings, it acts directly on a specific group of liver cells and improves how the organ functions, regardless of how many pounds a patient loses.
Why scientists were looking in the wrong direction for years
For years, the prevailing view was that liver cells did not carry the receptors semaglutide could bind to. That led to the assumption that the drug had no direct route to the liver and that all of its positive effects were simply the result of weight loss and improved metabolism.
But clinical trials were showing something that did not fully fit that explanation. Patients who lost only a small amount of weight showed similar improvements in liver inflammation, scarring, and liver enzyme levels as those who lost much more.
“In clinical trials, we saw that patients who lost very little weight had the same reductions in liver inflammation, scarring, and enzyme levels as those who lost a great deal. Now we know why,” explains Dr. Daniel Drucker of the Lunenfeld‑Tanenbaum Research Institute.
Just three percent of cells, yet they may be driving everything
Dr. Maria Gonzalez‑Rellan and her team identified two types of liver cells carrying receptors for semaglutide: liver sinusoidal endothelial cells (LSECs) and immune T cells. The key players turned out to be the LSECs.
These cells make up only about three percent of the liver’s cell volume, but according to the study, they are the main driver of the entire effect. They line the smallest blood vessels in the liver and act like a fine molecular sieve, filtering substances passing between the bloodstream and liver tissue.
When semaglutide binds to them, it changes the activity of their genes and the cells begin releasing anti‑inflammatory molecules. Those molecules then influence the broader liver environment and push it closer to a healthy state.
Key tests showed the effect is not just about weight loss
Researchers tested their theory in mice with MASH, a severe form of fatty liver disease linked to metabolic dysfunction. It is a condition in which fat builds up in the liver, inflammation is triggered, and scarring begins to form. In more serious cases, the disease can lead to cirrhosis or liver failure.
The first experiment showed that semaglutide was able to reverse MASH even in mice that lacked the brain receptors controlling appetite. In other words, the effect on the liver appeared even without the mechanism through which the drug usually helps reduce food intake.
The second test was even more convincing. Mice lacking receptors specifically in LSEC cells showed no improvement in liver health even after losing 20 percent of their body weight. That suggests weight loss alone is not enough to explain what semaglutide is doing in the liver.
Weight may no longer be the only measure of success
This discovery could also change how doctors think about GLP‑1 drugs. Until now, the focus has largely been on doses needed to achieve significant weight loss, which often comes with side effects.
If it turns out that the liver benefits even at lower doses, that could eventually mean gentler treatment, fewer side effects, and possibly lower costs for patients. For now, though, this is not a recommendation to change treatment immediately. It is an important shift in how we understand this class of drugs.
“We’re not saying weight loss is unimportant, because many things improve when patients lose weight. But we now know that body weight should not be the only measure of success, because GLP‑1 drugs improve liver health whether a patient loses weight or not,” adds Dr. Drucker.
