Semaglutide Protects Liver Independently of Weight Loss via Endothelial GLP-1 Receptors

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH), are global health burdens with limited treatment options. Semaglutide, a GLP-1 receptor agonist, has shown promise in improving liver health, often attributed to its profound weight-loss effects. However, the precise mechanisms and whether its hepatoprotective benefits can occur independently of weight reduction have remained unclear, particularly regarding specific cellular targets within the liver.

Semaglutide treatment significantly improved liver histology and function even in the absence of substantial weight loss. In the pair-fed group, semaglutide reduced hepatic steatosis by 43% (p<0.001) and inflammation by 35% (p<0.01) compared to untreated controls, despite similar body weights. This was accompanied by a 2.5-fold decrease in circulating ALT levels (p<0.001). The most striking finding was observed in the genetic models: > Semaglutide's hepatoprotective effects, including reductions in liver fat and fibrosis, were completely abrogated in mice lacking GLP-1 receptors on intrahepatic sinusoidal endothelial cells, demonstrating that these specific cells are essential mediators of its direct liver benefits. Furthermore, semaglutide increased eNOS (endothelial nitric oxide synthase) activity by 1.8-fold (p<0.05) in wild-type LSECs, a key factor in maintaining sinusoidal health, an effect absent in LSEC-GLP-1R-KO mice.