Inhibition of cholesterol synthesis by mevinolin stimulates low density lipoprotein receptor activity in human monocyte-derived macrophages

Abstract

Mevinolin inhibited the incorporation of [ 14C]acetate into cholesterol by human monocyte-derived macrophages (HMD macrophages) when both mevinolin and [ 14C]acetate were added simultaneously to the culture medium. Longer incubation with mevinolin, 24 h, led to a marked increase in the degradation of [ 125I]low density lipoprotein (LDL) via the high affinity receptor for LDL by HMD macrophages. Furthermore, this increased LDL receptor activity in cells incubated for 24 h with mevinolin and lipoprotein-depleted serum (LPDS) led to a nearly 3-fold increase in the formation of cholesteryl esters when these cells were then incubated with LDL for 24 h. Continuous exposure to mevinolin did not result in a constant increase in LDL receptor activity. Cells exposed to mevinolin for 24 h on day 3 had increased LDL receptor activity, but continuous exposure to mevinolin with 5% human serum (HS) from day 3–9 resulted in degradation of [ 125I]LDL at the same rate as observed in cells incubated with 5% HS alone. Cholesterol synthesis from [ 14C]acetate was decreased in cells incubated for 24 h in 5% HS + mevinolin compared with 5% HS alone, and in 10% LPDS + mevinolin compared with 10% LPDS alone; however, cells incubated with LPDS + mevinolin synthesized cholesterol at higher rates than did cells cultured in 5% HS alone. Continuous culture with 5% HS + mevinolin for 5 days resulted in cholesterol synthesis at control levels. These data show that following inhibition of cholesterol synthesis by mevinolin, HMD macrophages maintain cholesterol homeostasis by increasing LDL receptor activity to obtain cholesterol from LDL.