The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.
basic_science · Level V
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- Record sourced from PubMed, PMID 41985454.
- Also identified by DOI 10.1016/j.cmet.2026.03.011.
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Abstract
Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1r<sup>Wnt1-/-</sup> mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8<sup>+</sup> T cells. EC Glp1r deletion in Glp1r<sup>Tie2-/-</sup> mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r<sup>+</sup> LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r<sup>+</sup> LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.