HMG-COA REDUCTASE INHIBITORS REDUCE ACETYL LDL ENDOCYTOSIS IN MOUSE PERITONEAL-MACROPHAGES

We previously reported that mevalonate starvation elicited by hydroxym ethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced chole sterol accumulation promoted in murine macrophages by acetylated LDL ( AcLDL). In the present study we investigated the cellular mechanism of this effect. Our results indicate that the HMG-CoA reductase inhibito rs fluvastatin and simvastatin reduce, in a concentration-dependent ma nner, more then 50% of the I-125-AcLDL degradation by macrophages. Thi s effect was not due to a decrease of lysosomal enzyme activity, and i t was paralleled by the retention of AcLDL-associated cholesteryl este r in the incubation medium. The ability of fluvastatin to inhibit AcLD L degradation was completely overcome by mevalonate and its derivative geranylgeraniol. Evaluation at 4 degrees C of I-125-AcLDL binding to plasma membrane suggested that the inhibitory effect of fluvastatin on lipoprotein catabolism was not due to a decreased expression of scave nger receptors. Fluorescent microscope analysis of cellular internaliz ation of AcLDL labeled with the fluorochrome 3,3'-dioctadecyl indocarb ocyanine demonstrated that fluvastatin inhibits lipoprotein endocytosi s, an effect reversed by mevalonate. Studies performed with native I-1 25-LDL indicated that fluvastatin did not inhibit but rather increased the degradation of LDL taken up by the normal LDL receptor. These res ults exclude a generalized depression of the cellular endocytotic acti vity by the drug. The ability of fluvastatin to reduce AcLDL catabolis m and cholesterol esterification was more pronounced in cholesterol-en riched macrophages compared with normal cells. In conclusion, the pres ent results demonstrate that HMG-CoA reductase inhibitors may reduce t he in vitro cholesterol accumulation in macrophages by inhibiting AcLD L endocytosis.