Researchers at Sinai Health have found that semaglutide 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 two billion worldwide by 2050. 

“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 Dr Daniel Drucker, a senior investigator at the Lunenfeld-Tanenbaum Research Institute and University Professor of Medicine at the University of Toronto, who led the study.

As well as type 2 diabetes and obesity, semaglutide and other GLP-1 medicines have been approved for other conditions including MASH, for metabolic dysfunction-associated steatohepatitis. MASH is a severe form of fatty liver disease in which fat buildup, inflammation and tissue scarring can lead to cirrhosis and liver failure. 

Dr Drucker’s 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. 

Calming the inflammatory environment 

Postdoctoral fellow Dr Maria Gonzalez-Rellan spearheaded the work that combined 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 3% 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.  

Dr 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% 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 specialised 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,” added Dr Drucker.