OXIDATIVELY MODIFIED HDLS ARE POTENT INHIBITORS OF CHOLESTEROL-BIOSYNTHESIS IN HUMAN SKIN FIBROBLASTS

Several biological properties of lipoproteins are modified by oxidative reactions. Modified lipoproteins are rapidly degraded by macrophages, and this is likely to be a major pathway for the formation of foam cells in the early phases of atherosclerosis. The effect of modification on other aspects of cholesterol homeostasis has, however, received lesser attention. In this study, the influence of copper ion- as well as rat aortic smooth muscle cell-oxidation-modified high density lipoprotein (HDL) on cholesterol biosynthesis in human skin fibroblasts has been investigated. Modified lipoproteins eluted at higher ionic strength than did control HDL on a Mono-Q 515 anion-exchange column. However, only copper ion-modified HDLs displayed greater electrophoretic mobility than did control lipoproteins on agarose gel electrophoresis. Both control and modified HDLs decreased cholesterol esterification in fibroblasts. On the other hand, whereas control HDLs were virtually ineffective in modulating cholesterol biosynthesis, modified HDLs had a significant suppressing effect. This was observed in normal as well as low density lipoprotein (LDL) receptor-defective fibroblasts, which are unresponsive to the LDL-mediated downregulation of cholesterol synthesis. These results are consistent with the concept that oxidative modification of HDLs drastically alters their effect on cholesterol homeostasis in fibroblasts. The data furthermore suggest the existence of a lipoprotein pathway for cholesterol biosynthesis regulation that is independent of the LDL receptor-mediated pathway. Downregulation of cholesterol biosynthesis would be a new function for oxidatively modified lipoproteins.