Macrophage cholesteryl ester hydrolases and hormone-sensitive lipase prefer specifically oxidized cholesteryl esters as substrates over their non-oxidized counterparts

The oxidative modification of low-density lipo:protein (LDL) has been impli cated as a pro-atherogenic process in the pathogenesis of atherosclerosis. Macrophages rapidly take up oxidized LDL via scavenger-receptor-mediated pa thways and thereby develop into lipid-laden foam cells. The uptake mechanis m has been studied extensively and several types of scavenger receptors hav e been identified. In contrast, the intracellular fate of oxidized LDL lipi ds is less well investigated. We studied the degradation of specifically ox idized cholesteryl esters by murine macrophages using an HPLC-based assay, and found that oxidized substrates are hydrolysed preferentially from a 1:1 molar mixture of oxidized and non-oxidized cholesteryl esters. This effect was observed at both neutral and acidic pH. Similar results were obtained with lysates of human monocytes and with pure recombinant human hormone-sen sitive lipase. These data suggest that the intracellular oxidation of chole steryl esters may facilitate intracellular cholesteryl ester hydrolysis, an d thus may represent an anti-atherogenic process.