Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
Endocrinol Metab (Seoul). 2021 Feb;36(1):157-170. doi: 10.3803/EnM.2020.781. Epub 2021 Feb 24.
Glucagon-like peptide-1 (GLP-1) analogues regulate glucose homeostasis and have anti-inflammatory properties, but cause gastrointestinal side effects. The fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism that has poor pharmacokinetic properties, including a short half-life. To overcome these limitations, we investigated the effect of a low-dose combination of a GLP-1 analogue and FGF21 on atherosclerosis-related molecular pathways.
C57BL/6J mice were fed a high-fat diet for 30 weeks followed by an atherogenic diet for 10 weeks and were divided into four groups: control (saline), liraglutide (0.3 mg/kg/day), FGF21 (5 mg/kg/day), and low-dose combination treatment with liraglutide (0.1 mg/kg/day) and FGF21 (2.5 mg/kg/day) (n=6/group) for 6 weeks. The effects of each treatment on various atherogenesisrelated pathways were assessed.
Liraglutide, FGF21, and their low-dose combination significantly reduced atheromatous plaque in aorta, decreased weight, glucose, and leptin levels, and increased adiponectin levels. The combination treatment upregulated the hepatic uncoupling protein-1 (UCP1) and Akt1 mRNAs compared with controls. Matric mentalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated and phosphorylated Akt (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-ERK) were upregulated in liver of the liraglutide-alone and combination-treatment groups. The combination therapy also significantly decreased the proliferation of vascular smooth muscle cells. Caspase-3 was increased, whereas MMP-9, ICAM-1, p-Akt, and p-ERK1/2 were downregulated in the liraglutide-alone and combination-treatment groups.
Administration of a low-dose GLP-1 analogue and FGF21 combination exerts beneficial effects on critical pathways related to atherosclerosis, suggesting the synergism of the two compounds.
胰高血糖素样肽-1（GLP-1）类似物可调节葡萄糖稳态，具有抗炎作用，但会引起胃肠道副作用。成纤维细胞生长因子 21（FGF21）是一种调节脂质和葡萄糖代谢的激素，但其药代动力学特性较差，半衰期较短。为了克服这些局限性，我们研究了低剂量 GLP-1 类似物和 FGF21 联合应用对动脉粥样硬化相关分子途径的影响。
C57BL/6J 小鼠喂食高脂肪饮食 30 周，随后喂食致动脉粥样硬化饮食 10 周，分为 4 组：对照组（生理盐水）、利拉鲁肽（0.3mg/kg/天）、FGF21（5mg/kg/天）和低剂量联合治疗组（利拉鲁肽 0.1mg/kg/天）和 FGF21（2.5mg/kg/天）（每组 6 只）治疗 6 周。评估每种治疗方法对各种动脉粥样硬化相关途径的影响。
利拉鲁肽、FGF21 和它们的低剂量联合治疗显著减少了主动脉粥样斑块，降低了体重、血糖和瘦素水平，增加了脂联素水平。与对照组相比，联合治疗组肝脏解偶联蛋白 1（UCP1）和 Akt1 mRNA 上调。基质金属蛋白酶-9（MMP-9）、单核细胞趋化蛋白-1（MCP-1）和细胞间黏附分子-1（ICAM-1）下调，肝内磷酸化 Akt（p-Akt）和磷酸化细胞外信号调节激酶（p-ERK）上调。联合治疗组还显著抑制血管平滑肌细胞增殖。 caspase-3 增加，而 MMP-9、ICAM-1、p-Akt 和 p-ERK1/2 在利拉鲁肽单药和联合治疗组下调。
低剂量 GLP-1 类似物和 FGF21 联合给药对与动脉粥样硬化相关的关键途径有有益影响，提示两种化合物具有协同作用。
