Salicylate improves macrophage cholesterol homeostasis via activation of Ampk
Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. The AMP-activated protein kinase (Ampk) is a highly conserved serine/threonine kinase that regulates many aspects of lipid and energy metabolism, although its specific role in controlling macro...
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doaj-969fbeecc8a94280ace39dc0750fbf2d2021-04-28T05:57:19ZengElsevierJournal of Lipid Research0022-22752015-05-0156510251033Salicylate improves macrophage cholesterol homeostasis via activation of AmpkMorgan D. Fullerton0Rebecca J. Ford1Chelsea P. McGregor2Nicholas D. LeBlond3Shayne A. Snider4Stephanie A. Stypa5Emily A. Day6Šárka Lhoták7Jonathan D. Schertzer8Richard C. Austin9Bruce E. Kemp10Gregory R. Steinberg11To whom correspondence should be addressed.; Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada; Department of Medicine, and Departments of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada; To whom correspondence should be addressed.Divisions of Endocrinology and Metabolism McMaster University, Hamilton, CanadaDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, CanadaDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, CanadaDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, CanadaDivisions of Endocrinology and Metabolism McMaster University, Hamilton, CanadaDivisions of Endocrinology and Metabolism McMaster University, Hamilton, CanadaHamilton Centre for Kidney Research, St. Joseph's Healthcare Hamilton, Hamilton, Canada; Nephrology, McMaster University, Hamilton, CanadaDepartment of Medicine, and Departments of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Canada; Pediatrics, McMaster University, Hamilton, CanadaHamilton Centre for Kidney Research, St. Joseph's Healthcare Hamilton, Hamilton, Canada; Nephrology, McMaster University, Hamilton, CanadaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, AustraliaTo whom correspondence should be addressed.; Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada; Department of Medicine, and Departments of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Canada; To whom correspondence should be addressed.Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. The AMP-activated protein kinase (Ampk) is a highly conserved serine/threonine kinase that regulates many aspects of lipid and energy metabolism, although its specific role in controlling macrophage cholesterol homeostasis remains unclear. We sought to address this question by testing the effects of direct Ampk activators in primary bone marrow-derived macrophages from Ampk β1-deficient (β1−/−) mice. Macrophages from Ampk β1−/− mice had enhanced lipogenic capacity and diminished cholesterol efflux, although cholesterol uptake was unaffected. Direct activation of Ampk β1 via salicylate (the unacetylated form of aspirin) or A-769662 (a small molecule activator), decreased the synthesis of FAs and sterols in WT but not Ampk β1−/− macrophages. In lipid-laden macrophages, Ampk activation decreased cholesterol content (foam cell formation) and increased cholesterol efflux to HDL and apoA-I, effects that occurred in an Ampk β1-dependent manner. Increased cholesterol efflux was also associated with increased gene expression of the ATP binding cassette transporters, Abcg1 and Abca1. Moreover, in vivo reverse cholesterol transport was suppressed in mice that received Ampk β1−/− macrophages compared with the WT control. Our data highlight the therapeutic potential of targeting macrophage Ampk with new or existing drugs for the possible reduction in foam cell formation during the early stages of atherosclerosis.http://www.sciencedirect.com/science/article/pii/S0022227520312426cholesterol effluxadenosine 5′-monophosphate-activated protein kinaselipid homeostasisatherosclerosisreverse cholesterol transport |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Morgan D. Fullerton Rebecca J. Ford Chelsea P. McGregor Nicholas D. LeBlond Shayne A. Snider Stephanie A. Stypa Emily A. Day Šárka Lhoták Jonathan D. Schertzer Richard C. Austin Bruce E. Kemp Gregory R. Steinberg |
spellingShingle |
Morgan D. Fullerton Rebecca J. Ford Chelsea P. McGregor Nicholas D. LeBlond Shayne A. Snider Stephanie A. Stypa Emily A. Day Šárka Lhoták Jonathan D. Schertzer Richard C. Austin Bruce E. Kemp Gregory R. Steinberg Salicylate improves macrophage cholesterol homeostasis via activation of Ampk Journal of Lipid Research cholesterol efflux adenosine 5′-monophosphate-activated protein kinase lipid homeostasis atherosclerosis reverse cholesterol transport |
author_facet |
Morgan D. Fullerton Rebecca J. Ford Chelsea P. McGregor Nicholas D. LeBlond Shayne A. Snider Stephanie A. Stypa Emily A. Day Šárka Lhoták Jonathan D. Schertzer Richard C. Austin Bruce E. Kemp Gregory R. Steinberg |
author_sort |
Morgan D. Fullerton |
title |
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk |
title_short |
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk |
title_full |
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk |
title_fullStr |
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk |
title_full_unstemmed |
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk |
title_sort |
salicylate improves macrophage cholesterol homeostasis via activation of ampk |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2015-05-01 |
description |
Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. The AMP-activated protein kinase (Ampk) is a highly conserved serine/threonine kinase that regulates many aspects of lipid and energy metabolism, although its specific role in controlling macrophage cholesterol homeostasis remains unclear. We sought to address this question by testing the effects of direct Ampk activators in primary bone marrow-derived macrophages from Ampk β1-deficient (β1−/−) mice. Macrophages from Ampk β1−/− mice had enhanced lipogenic capacity and diminished cholesterol efflux, although cholesterol uptake was unaffected. Direct activation of Ampk β1 via salicylate (the unacetylated form of aspirin) or A-769662 (a small molecule activator), decreased the synthesis of FAs and sterols in WT but not Ampk β1−/− macrophages. In lipid-laden macrophages, Ampk activation decreased cholesterol content (foam cell formation) and increased cholesterol efflux to HDL and apoA-I, effects that occurred in an Ampk β1-dependent manner. Increased cholesterol efflux was also associated with increased gene expression of the ATP binding cassette transporters, Abcg1 and Abca1. Moreover, in vivo reverse cholesterol transport was suppressed in mice that received Ampk β1−/− macrophages compared with the WT control. Our data highlight the therapeutic potential of targeting macrophage Ampk with new or existing drugs for the possible reduction in foam cell formation during the early stages of atherosclerosis. |
topic |
cholesterol efflux adenosine 5′-monophosphate-activated protein kinase lipid homeostasis atherosclerosis reverse cholesterol transport |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520312426 |
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