Cholesterol oxides inhibit cholesterol esterification by lecithin:cholesterol acyl transferase

Cholesterol oxides are atherogenic and can affect the activity of diverse important enzymes for the lipidic metabolism. The effect of 7 beta-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol, cholestan-3 beta.5 alpha.6 beta-trol,5,6 beta-cpoxycholesterol, 5,6 alpha-cpoxycholesterol and 7 alpha-hydroxycholesterol on esterification of cholesterol by lecithin cholesterol acyl transferase (LCAT, EC 2.3.1 43) and the transfer of esters of cholesterol oxides from high density lipoprotein (HDL) to low density lipoproteins (LDL) and very low density lipoporteins (VLDL) by cholesteryl ester transfer protin (CETP) was investigated HDL enriched with increasing concentrations of cholesterol oxides was incubated with fresh plasma as source of LCAT. Cholesterol and cholesterol oxides esterification was followed by measuring the consumption of respective free sterol and oxysterols. Measurements of cholesterol and cholesterol oxides were done by gas-chromatography. (14)C-cholesterol oxides were incorporated into HDL(2) and HDL(3) subfractions and then incubated with fresh plasma containing LCAT and CETP. The transfer of cholesterol oxide esters was followed by measuring the (14)C-cholesterol oxide-derived esters transferred to LDL and VLDL. All the cholesterol oxides studied were esterified by LCAT after incorporation into HDL particles, competing with cholesterol by LCAT. Cholesterol esterification by LCAT was inversely related to the cholesterol oxide concentration. The esterification of (14)C-cholesterol oxides was higher in HDL(3) and the transfer of the derived esters was greater from HDL(2) to LDL and VLDL. The results suggest that cholesterol oxides may exert part of their atherogenic effect by inhibiting cholesterol esterification on the HDL surface and therby disturbing reverse cholesterol transport.