Stimulation of phospholipid and cholesterol ester synthesis by platelet-derived growth factor in normal and homozygous familial hypercholesterolemia human skin fibroblasts

Abstract

Pure human platelet-derived growth factor at nanogram levels stimulates cholesterol ester, phospholipid and DNA synthesis in normal and familial hypercholesterolemia mutant human skin fibroblasts. Stimulation of DNA synthesis did not begin until 15–24 h after addition of platelet-derived growth factor to quiescent normal and FH mutant fibroblasts. In contrast, stimulation of [ 3H]oleic acid incorporation into cholesterol ester and phospholipid was evident 3–6 h after the addition of platelet-derived growth factor. In the normal cells, the rate of cholesterol ester synthesis was maximal at 24 h, then rapidly declined. Compared to the normal cells, cholesterol esterification was much lower in the FH cells; however, platelet-derived growth factor stimulated the rate of [ 3H]oleic acid incorporation into cholesterol ester by 5-fold, 31 h after addition of the growth factor. The stimulation of [ 3H]oleic acid incorporation into cholesterol ester by platelet-derived growth factor was inhibited in both normal and FH mutant skin fibroblasts by progesterone, an inhibitor of acyl-CoA: cholesterol acyltransferase. The rate of cholesterol ester synthesis in the normal cells increased as the concentration of platelet-poor plasma or low density lipoprotein (LDL) was increased, especially in the presence of platelet-derived growth factor. Linearization of the LDL dose-response curve indicated that platelet-derived growth factor increased the rate rather than the affinity of the overall cholesterol esterification system. The rate of cholesterol esterification in the FH mutant cells was highest in the absence of LDL or at low levels of platelet-poor plasma. Consequently, platelet-derived growth factor can stimulate cholesterol ester synthesis by LDL- and non-LDL-mediated processes.