加拿大西奈山医院Daniel J. Drucker小组宣布他们的研究显示，西马鲁肽的减肥非依赖性肝保护作用是由肝内窦内皮GLP-1受体协调的。2026年4月14日出版的《细胞—代谢》发表了这项成果。

课题组人员研究了西马鲁肽对代谢功能障碍相关脂肪性肝炎（MASH）小鼠的作用。在Glp1rWnt1 / 小鼠抵抗GLP-1RA诱导的体重减轻，西马鲁肽改善脂肪变性，纤维化和免疫重塑。GEM-X Flex-seq将Glp1r表达定位于肝正中周窦样内皮细胞（ECs）和CD8⁺ T细胞。Glp1rTie2/小鼠或AAV8-Cre介导的肝EC Glp1r敲低基本上取消了西马鲁肽的肝脏益处，尽管保留了体重减轻。转录组学分析显示，Glp1r⁺ LSECs在MASH中采用一种应激反应表型，这种表型被信号肽逆转。Glp1r⁺ LSECs是与VWF、SELE、CEACAM和BMP等损伤和修复相关的semaglu肽调控回路的主要参与者。分子分析揭示了信号肽协调的转录和蛋白质水平的疾病特征逆转。总之，MASH的数据主题模型揭示了一个EC特异性的、减肥无关的、信号肽调节的、GLP-1R依赖的肝内网络，可改善肝脏健康。

研究人员表示，胰高血糖素样肽-1 （GLP-1）药物通过减肥依赖和独立作用改善代谢性肝病。

附：英文原文

Title: The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors

Author: Maria J. Gonzalez-Rellan, Cristina Riobello, Susanna Fang, Eloisa Martins da Silva, Jacqueline A. Koehler, Rui Shang, Rola Hammoud, Xiemin Cao, Marta Varela-Rey, Daniel J. Drucker

Issue&Volume: 2026-04-14

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 Glp1rWnt1/ 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+ T cells. EC Glp1r deletion in Glp1rTie2/ mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide’s hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ 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.

DOI: 10.1016/j.cmet.2026.03.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(26)00105-1