Department of Biochemistry and Structural Biology and.
Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
JCI Insight. 2022 Sep 8;7(17):e155552. doi: 10.1172/jci.insight.155552.
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.
心血管疾病，特别是动脉粥样硬化及其并发症，是导致死亡的主要原因。用氨来酸抑制非经典 IκB 激酶 TANK 结合激酶 1 和 IKKε，可恢复糖尿病小鼠和人类患者的胰岛素敏感性和血糖稳态。在这里，我们报告氨来酸可改善西方饮食喂养（WD 喂养）Ldlr-/-小鼠的饮食诱导的高甘油三酯血症和高胆固醇血症，并可预防动脉粥样硬化形成。氨来酸通过协同作用改善血脂异常、炎症和血管功能障碍，该协同作用涉及上调胆汁酸合成以增加胆固醇排泄。转录组谱分析表明关键胆汁酸合成基因的表达升高。此外，我们发现氨来酸可减轻 WD 诱导的动脉粥样硬化过程中的单核细胞增多症、嗜酸性粒细胞增多症和血管功能障碍。这些发现表明氨来酸有作为治疗高胆固醇血症和动脉粥样硬化的潜力。
