The TBK1/IKKe Inhibitor Amlexanox Improves Dyslipidemia and Prevents Atherosclerosis

Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the non-canonical IkB kinases TBK1 and IKKe with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human subjects. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet (WD)-fed Ldlr-/- mice, and protects against atherogenesis. Amlexanox ameliorates dyslipidemia, inflammation and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrates an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuates monocytosis, eosinophilia and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a new therapy for hypercholesterolemia and atherosclerosis. Overall design: Bulk RNA-seq of RNA isolated from vehicle or amlexanox treated Ldlr-/- mice fed Western diet.