The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis

Area of Science:

• Biochemistry
• Cardiovascular Research
• Pharmacology

Background:

• Cardiovascular diseases, including atherosclerosis, are a major cause of mortality.
• Amlexanox inhibits TANK-binding kinase 1 (TBK1) and IKKε, showing promise in metabolic disorders.

Purpose of the Study:

• To investigate amlexanox's effects on diet-induced hyperlipidemia and atherosclerosis in Ldlr-/- mice.
• To elucidate the mechanisms underlying amlexanox's lipid-lowering and anti-atherogenic properties.

Main Methods:

• Mice were fed a Western diet (WD) to induce hyperlipidemia and atherosclerosis.
• Amlexanox treatment was administered, followed by assessment of lipid profiles, inflammation markers, and atherosclerotic lesion development.
• Transcriptomic profiling was used to analyze gene expression changes, particularly in bile acid synthesis pathways.

Main Results:

• Amlexanox significantly improved hypertriglyceridemia and hypercholesterolemia in WD-fed mice.
• The drug upregulated key genes involved in bile acid synthesis, promoting cholesterol excretion.
• Amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction associated with atherosclerosis.

Conclusions:

• Amlexanox demonstrates significant therapeutic potential for managing hypercholesterolemia and atherosclerosis.
• Its mechanism involves enhanced cholesterol excretion via increased bile acid synthesis.
• Amlexanox offers a promising new avenue for treating cardiovascular diseases linked to lipid dysregulation.