OXIDATION-PRODUCTS OF CHOLESTERYL LINOLEATE ARE RESISTANT TO HYDROLYSIS IN MACROPHAGES, FORM COMPLEXES WITH PROTEINS, AND ARE PRESENT IN HUMAN ATHEROSCLEROTIC LESIONS

Accumulation of the insoluble lipid-protein complex, ceroid, is a char acteristic of atherosclerotic plaques. To determine whether deficient processing of cholesteryl esters in oxidized (ox) low density lipoprot ein (LDL) contributes to ceroid formation, we studied the hydrolysis o f internalized [H-3] cholesteryl linoleate (CL) in oxLDL by mouse peri toneal macrophages (MPM). The hydrolysis by MPM of [H-3]CL incorporate d into oxLDL or LDL did not differ, suggesting that products of lipid and/or apoB oxidation had no impact on the lysosomal hydrolysis of [H- 3]CL. TO evaluate the hydrolysis of oxCL by MPM, we subjected extensiv ely ox[H-3] CL to fractionation by TLC. The predominant fraction (D) c onsisted of sterols and oxysterols esterified to scission products of oxidized fatty acids containing terminal carbonyl groups, i.e., lipid core aldehydes. The extent of hydrolysis of [H-3]-fraction D by MPM cu ltures, as well as by MPM extracts at pH 4.0, was significantly reduce d when compared to the hydrolysis of intact [H-3] CL. Fraction D also formed complexes with serum proteins, and the purified core aldehyde, cholesteryl 9-oxononanoate reacted with epsilon-amino group of lysines . Finally, several cholesteryl ester aldehydes were detected in lipid extracts of human atheroma. These results suggest that decomposition p roducts of extensively oxidized cholesteryl linoleate that are also pr esent in atherosclerotic lesions, are not adequately degraded by mouse peritoneal macrophage lysosomes and could interact with proteins to f orm ceroid.