D. Ibrahim1, I. Kuziez1, S. Hafezi1, L. Belaygorod1, B. Arif1, C. Semenkovich2, M. Zayed1 1Washington University, Surgery, St. Louis, MO, USA 2Washington University, Endocrinology, St. Louis, MO, USA
Introduction:
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, used for treating non-alcoholic fatty liver disease (NAFLD) and obesity, also significantly improves cardiovascular endpoints. While its beneficial effects on liver steatosis and metabolic parameters have been reported, the mechanisms underlying the impact of semaglutide on cardiovascular disease is still not fully understood. Our team previously demonstrated that circulating Fatty Acid Synthase (cFAS) can impact macrophage foam cell formation and correlates with severity of peripheral arterial disease. We hypothesized that semaglutide can impact cFAS activity, leading to reduced foam cell formation.
Methods:
Five mice aged 6-7 weeks from each strain (Apoe-/- and C57BL/6) received daily subcutaneous injections of either semaglutide or PBS for six weeks. Semaglutide dosage was escalated from 3 nmol/kg at day 1-3, 6 nmol/kg at day 4-8, 9 nmol/kg at day 9-11, 12 nmol/kg at day 12-14 to the final dose of 15 nmol/kg at day 15 until termination. Throughout the treatment, all mice were fed an adjusted calories diet (42% from fat) to induce metabolic stress and promote lipid accumulation. To assess hepatic lipid content, Oil Red O staining was employed to quantify lipid droplets in liver tissue. Fatty acid synthase (FAS) gene expression was analyzed using RT-PCR. Furthermore, an FAS activity assay was performed to evaluate the enzyme functional status.
Results:
During the six-week treatment period, there were no drug-related changes in body weight or liver weight across all groups. ELISA analysis revealed comparable FAS content in the liver across all groups, regardless of treatment status. However, hepatic FAS expression was significantly downregulated in semaglutide-treated C57BL/6 (p=0.0012) and Apoe-/- (p=0.0006) mice compared to their respective controls. Furthermore, semaglutide administration resulted in a reduction in hepatic lipid droplet area in both C57BL/6 (p=0.0089) and Apoe-/- (p=0.0706) mice (Figure 1B). Circulating FAS (cFAS) activity in C57BL/6J mouse serum decreased following semaglutide treatment (p=0.046) (Figure 1C).
Conclusion:
Semaglutide impacts cFAS activity and may reduce liver fatty acid synthesis in Apoe-/- and C57BL/6 mice. These findings are consistent with the use of semaglutide as a promising therapeutic agent for managing liver steatosis and potentially atherosclerosis by targeting FAS. Further research is needed to fully understand the underlying mechanisms and clinical implications of these effects.