The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis

Peng Zhao, Xiaoli Sun, Zhongji Liao, Hong Yu, Dan Li, Zeyang Shen, Christopher K. Glass, Joseph L. Witztum, Alan R. Saltiel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere155552
JournalJCI Insight
Volume7
Issue number17
DOIs
StatePublished - Sep 8 2022

ASJC Scopus subject areas

  • Medicine(all)

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