Abstract 533: Salicylate Restores Macrophage Cholesterol Homeostasis via Activation of AMP-Activated Protein Kinase

Objectives: Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. 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 foam cell cholesterol homeostasis remains unclear. Methods: We sought to address this question by testing the effects of AMPK-specific activators in primary bone marrow-derived macrophages from AMPK β1-deficient (β1-/-) mice. Results: Macrophages from AMPK β1-/- mice had enhanced lipogenic potential and diminished cholesterol efflux, although cholesterol uptake was unaffected. Specific activation of Ampk β1 via salicylate (the unacetylated form of aspirin) or A-769662 (a small molecule activator), decreased the synthesis of both fatty acids and sterols in WT but not AMPK β1-/- macrophages. In lipid-laden macrophage foam cells, salicylate and A-769662 decreased cholesterol uptake 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 and protein expression of the ATP binding cassette transporters, ABCG1 and ABCA1. Moreover, in vivo reverse cholesterol transport was significantly suppressed in mice that received AMPK β1-/- macrophages compared to WT control. Conclusion: Our data highlight the therapeutic potential of targeting macrophage AMPK with new or existing drugs for the restoration of cholesterol homeostasis during the early stages of atherosclerosis.