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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536260/ https://www.ncbi.nlm.nih.gov/pubmed/35917178 http://dx.doi.org/10.1172/jci.insight.155552 |
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author | Zhao, Peng Sun, Xiaoli Liao, Zhongji Yu, Hong Li, Dan Shen, Zeyang Glass, Christopher K. Witztum, Joseph L. Saltiel, Alan R. |
author_facet | Zhao, Peng Sun, Xiaoli Liao, Zhongji Yu, Hong Li, Dan Shen, Zeyang Glass, Christopher K. Witztum, Joseph L. Saltiel, Alan R. |
author_sort | Zhao, Peng |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9536260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-95362602022-10-07 The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis Zhao, Peng Sun, Xiaoli Liao, Zhongji Yu, Hong Li, Dan Shen, Zeyang Glass, Christopher K. Witztum, Joseph L. Saltiel, Alan R. JCI Insight Research Article 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. American Society for Clinical Investigation 2022-09-08 /pmc/articles/PMC9536260/ /pubmed/35917178 http://dx.doi.org/10.1172/jci.insight.155552 Text en © 2022 Zhao et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhao, Peng Sun, Xiaoli Liao, Zhongji Yu, Hong Li, Dan Shen, Zeyang Glass, Christopher K. Witztum, Joseph L. Saltiel, Alan R. The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis |
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 | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536260/ https://www.ncbi.nlm.nih.gov/pubmed/35917178 http://dx.doi.org/10.1172/jci.insight.155552 |
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