title: Salicylate improves macrophage cholesterol homeostasis via activation of Ampk.
abstract: 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.
authors.affiliation: 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.
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.affiliation: Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Chelsea P
authors.initials: CP
authors.lastname: McGregor
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: LeBlond
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Shayne A
authors.initials: SA
authors.lastname: Snider
authors.affiliation: Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Stypa
authors.affiliation: Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Day
authors.affiliation: Hamilton Centre for Kidney Research, St. Joseph's Healthcare Hamilton, Hamilton, Canada Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lhoták
authors.affiliation: Department of Medicine, and Departments of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Canada Pediatrics, McMaster University, Hamilton, Canada.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.affiliation: Hamilton Centre for Kidney Research, St. Joseph's Healthcare Hamilton, Hamilton, Canada Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.affiliation: St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Divisions of Endocrinology and Metabolism McMaster University, Hamilton, Canada Department of Medicine, and Departments of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology*; D006706:Homeostasis; D050155:Lipogenesis; D018345:Mice, Knockout; D020156:Salicylic Acid / Q000494:pharmacology*
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D020536:Enzyme Activators; D002784:Cholesterol; C554549:Prkab1 protein, mouse; D055372:AMP-Activated Protein Kinases; D020156:Salicylic Acid
keywords: adenosine 5′-monophosphate-activated protein kinase; atherosclerosis; cholesterol efflux; lipid homeostasis; reverse cholesterol transport