Salicylate improves macrophage cholesterol homeostasis via activation of Ampk

Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory re- sponses. The AMP-activated protein kinase (Ampk) is a highly conserved serine/threonine kinase that regulates many aspects of lipid and energy metabolism, although its specifi c role in controlling macrophage cholesterol homeo- stasis remains unclear. We sought to address this question by testing the effects of direct Ampk activators in primary bone marrow-derived macrophages from Ampk 1-defi cient ( 1 / ) mice. Macrophages from Ampk 1 / mice had enhanced lipogenic capacity and diminished cholesterol effl ux, although cholesterol uptake was unaffected. Direct activation of Ampk 1 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 1 / macrophages. In lipid-laden macrophages, Ampk activation decreased cholesterol content (foam cell formation) and increased cholesterol effl ux to HDL and apoA-I, effects that occurred in an Ampk 1-dependent manner. Increased cholesterol effl ux 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 1 / macrophages compared with the WT con- trol. Our data highlight the therapeutic potential of tar- geting macrophage Ampk with new or existing drugs for the possible reduction in foam cell formation during the early stages of atherosclerosis. —Fullerton, M. D., R. J. Ford, C. P.