The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis
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 t...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.155552 |
| _version_ | 1797634404688855040 |
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| author | Peng Zhao Xiaoli Sun Zhongji Liao Hong Yu Dan Li Zeyang Shen Christopher K. Glass Joseph L. Witztum Alan R. Saltiel |
| author_facet | Peng Zhao Xiaoli Sun Zhongji Liao Hong Yu Dan Li Zeyang Shen Christopher K. Glass Joseph L. Witztum Alan R. Saltiel |
| author_sort | Peng Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:21Z |
| format | Article |
| id | doaj.art-fc33a0413edb494fa587070ff0965270 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:21Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-fc33a0413edb494fa587070ff09652702023-11-07T16:24:31ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-09-01717The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosisPeng ZhaoXiaoli SunZhongji LiaoHong YuDan LiZeyang ShenChristopher K. GlassJoseph L. WitztumAlan R. SaltielCardiovascular 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.https://doi.org/10.1172/jci.insight.155552Metabolism |
| spellingShingle | Peng Zhao Xiaoli Sun Zhongji Liao Hong Yu Dan Li Zeyang Shen Christopher K. Glass Joseph L. Witztum Alan R. Saltiel The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis JCI Insight Metabolism |
| title | The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| title_full | The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| title_fullStr | The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| title_full_unstemmed | The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| title_short | The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| title_sort | tbk1 ikkε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
| topic | Metabolism |
| url | https://doi.org/10.1172/jci.insight.155552 |
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