| Autor: |
Inia JA; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands.; Cardiology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center (LUMC), 2300 RC Leiden, The Netherlands., Stokman G; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Morrison MC; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Worms N; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Verschuren L; Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Caspers MPM; Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Menke AL; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., Petitjean L; PharmaNest Inc., Princeton, NJ 08540, USA., Chen L; PharmaNest Inc., Princeton, NJ 08540, USA., Petitjean M; PharmaNest Inc., Princeton, NJ 08540, USA., Jukema JW; Cardiology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center (LUMC), 2300 RC Leiden, The Netherlands.; Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands., Princen HMG; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands., van den Hoek AM; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The Netherlands. |
| Abstrakt: |
Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for the treatment of obesity as well. Semaglutide is postulated to be a promising candidate for the treatment of non-alcoholic steatohepatitis (NASH). Here, Ldlr-/-.Leiden mice received a fast-food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneous injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined, and hepatic transcriptome analysis was performed. In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p < 0.001) and inflammation (-73%, p < 0.001) and completely abolished microvesicular steatosis (-100%, p < 0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p < 0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for the treatment of hepatic steatosis and inflammation, while for the reversal of advanced fibrosis, combinations with other NASH agents may be necessary. |
