Effects of cholesterol oxides on LDL receptors in cultured rabbit aortic smooth muscle cells.

ABSTRACT

The efficiency of receptor-mediated low-density lipoprotein (LDL) uptake and degradation has been implicated in the development of atherosclerosis. It has previously been shown that cholesterol oxides have more effect on the feedback control of cholesterol biosynthesis than does cholesterol per se on a molecule-for-molecule basis. Cholesterol oxides may also modify the expression or function of the LDL receptors, resulting in alteration in cholesterol homeostasis. Rabbit aortic smooth muscle cells were preincubated in 5% lipoprotein-deficient medium for 24 hours and then incubated with 1 or 5 µg/ml purified cholesterol or cholesterol oxides, including 25-hydroxycholesterol, 7-ketocholesterol, cholestane-3ß,5α,6ß-triol, and cholesterol 5α, 6α-epoxide for 12 to 24 hours. The uptake of (125)I-LDL was significantly suppressed in a dose-dependent fashion to 67% of the control value by 25-hydroxycholesterol at 1 µg/ml and to 53% at 5 µg/ml after the 24-hour incubation period. Other cholesterol oxides also had inhibitory effects on the LDL uptake at 5 µg/ml. At these concentrations cholesterol oxides additionally inhibited cellular degradation of LDL and the fractional turnover rate of LDL was prolonged.