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

Abstract

The oxidative modification of low-density lipoprotein (LDL) has been implicated as a pro-atherogenic process in the pathogenesis of atherosclerosis. Macrophages rapidly take up oxidized LDL via scavenger-receptor-mediated pathways and thereby develop into lipid-laden foam cells. The uptake mechanism has been studied extensively and several types of scavenger receptors have been identified. In contrast, the intracellular fate of oxidized LDL lipids is less well investigated. We studied the degradation of specifically oxidized 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-sensitive lipase. These data suggest that the intracellular oxidation of cholesteryl esters may facilitate intracellular cholesteryl ester hydrolysis, and thus may represent an anti-atherogenic process.