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

The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis

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.

Authors

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

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Figure 2

Amlexanox increases bile acid synthesis and cholesterol excretion.

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Amlexanox increases bile acid synthesis and cholesterol excretion. (A–E)...
(A–E) Cholesterol metabolism in Ldlr–/– mice fed WD for 8 weeks, then orally gavaged with vehicle or amlexanox for 4 weeks with the continuation of WD feeding. (A) Fasting serum cholesterol. (B) Fasting serum triglycerides. (C) Serum 14C activity 2 hours after gavage of a mixture of cholesterol and 14C-cholesterol. (D) 3H activity in liver sterol fraction 2 hours after injection of 3H-acetate. (E–H) 14C activity in serum (E), liver lysate (F), bile (G), and feces (H) 21 hours after gavage of a mixture of cholesterol and 14C-cholesterol. (I–K) Transcriptomic profiling of livers from Ldlr–/– mice fed WD for 3 weeks, then orally gavaged with vehicle or amlexanox for 8 weeks with the continuation of WD feeding. (I) Scatterplot for RNA-Seq data: 1,042 genes had higher expression levels in Amx. (J) Functional annotation associated with genes expressed more highly in amlexanox-treated mice. (K) Relative expression values (Z-scaled log2[TPM+1]) for genes involved in bile acid metabolism. (L) Fecal bile acid levels in Ldlr–/– mice fed WD for 3 weeks, then orally gavaged with vehicle or amlexanox for 8 weeks with the continuation of WD feeding. Mean ± SEM. *, P < 0.05, Student’s unpaired t test. TPM, transcript per kilobase million.