GLP-1 medicine improves liver health independent of weight loss

Researchers at Sinai Health have found that semaglutide, the active ingredient in popular weight loss drugs that mimics the gut hormone GLP-1, acts directly on a subset of liver cells to improve organ function, and does so independently of weight loss. The finding challenges long-held assumptions about how GLP-1 medicines work in the liver and could reshape how physicians treat metabolic liver disease, a condition projected to affect nearly 2 billion worldwide by 2050.

For years, the liver benefits of semaglutide have puzzled scientists. The drug was known to lower blood sugar and promote weight loss, but patients’ livers were improving in ways that those effects alone could not explain. 

“We’ve seen in clinical trials that patients who lose very little weight see the same reductions in liver inflammation, scarring and enzyme levels as those who lose a great deal of weight. Now we know why,” said Daniel Drucker, a senior investigator at the Lunenfeld-Tanenbaum Research Institute and University Professor of endocrinology and metabolism at the University of Toronto’s Temerty Faculty of Medicine who led the study.

Drucker’s has been at the forefront of GLP-1 research since the 1980s when his pioneering discoveries helped lay the groundwork for the development of GLP-1 medicines.

After transforming treatment of type 2 diabetes and obesity, semaglutide and other GLP-1 medicines have been approved for other conditions including metabolic dysfunction-associated steatohepatitis (MASH). MASH is a severe form of fatty liver disease in which fat buildup, inflammation and tissue scarring can lead to cirrhosis and liver failure. It affects about 25 per cent of Canadian adults and because it is closely linked with obesity and type 2 diabetes, treatment typically includes lifestyle interventions to reduce weight.

Now Drucker and his team have revealed that semaglutide acts directly on the liver to reduce inflammation and scarring and improve organ function in a way that is independent of weight loss, as described in a paper published in Cell Metabolism.

Their finding overturns a prevailing assumption in the field that liver cells do not carry the receptor that semaglutide binds to, meaning the drug had no direct route to the organ.

Postdoctoral fellow Maria Gonzalez-Rellan spearheaded the work that combined sophisticated mouse models of MASH with deep molecular analyses of liver cells. Her work identified two cell types carrying semaglutide receptors: liver sinusoidal endothelial cells (LSECs) and immune T cells.

Although LSECs account for only about three per cent of liver cell volume, they proved to be the key driver of semaglutide’s liver benefits. LSECs line the tiniest blood vessels in the liver and are studded with pores that allow them to act as a molecular sieve, filtering substances passing between the liver and the bloodstream. Gonzalez-Rellan showed that semaglutide reversed MASH in mice that lacked the brain receptors controlling appetite demonstrating that weight loss is not required for liver benefits. In a further test, mice lacking LSEC receptors showed no liver improvement on semaglutide even after losing 20 per cent of their body weight. 

Detailed molecular analyses of liver cell types showed that semaglutide shifts gene activity in LSCEs, prompting them to release anti-inflammatory molecules that act on the broader liver environment, pushing it toward a state more closely resembling a healthy, disease-free liver.

“It turns out that the receptor responsible for these benefits is in a very specialized population of liver cells. And this receptor orchestrates the production of molecules that talk to many different types of liver cells to calm down the inflammatory environment that is the problem in metabolic disease,” said Drucker.

The findings carry practical implications. GLP-1 medicines have become widely prescribed, yet their mechanism of action in the body, beyond appetite suppression and blood sugar control, have remained incompletely understood. Knowing that semaglutide improves liver health independently of weight loss could influence prescribing decisions. Physicians may choose lower doses that avoid the side effects associated with the higher doses needed for significant weight loss, potentially also lowering costs for patients, said Drucker.

He added, “We're not saying weight loss isn't important because many things improve when patients lose weight. But we now know that weight shouldn't be the only measure of success, because GLP-1 medicines will improve liver health whether or not the patient loses weight.” 

This research was funded by grants from the Canadian Institutes of Health Research and a Sinai Health-Novo Nordisk Foundation Fund in Regulatory peptides.