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Studies were conducted to delineate in detail the effects of platelet-derived growth factor (PDGF) upon 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity in cultured human fibroblasts. PDGF has a variety of coordinated effects on low density lipoprotein (LDL) and cholesterol metabolism and on DNA synthesis in these cells. We have previously shown that there is a critical time period, 10 to 20 hours after PDGF addition to quiescent cells, when mevalonate (MVA) is required for DNA synthesis to occur. The present studies demonstrate that PDGF produces a biphasic stimulation of reductase activity in cultured fibroblasts: a peak at 4 to 6 hours, followed by a decline, and then a second smaller peak at 24 hours, concurrent with DNA synthesis. The stimulation of both peaks was PDGF concentration-dependent, although quantitative differences were observed. Proportionally similar, LDL concentration-dependent reductions in both peaks of reductase activity were also seen. PDGF stimulated cholesterol synthesis from acetate in intact cells reaching peak values after 24 to 28 hours. The two peaks of reductase activity stimulated by PDGF neither coincide with the critical time period when mevalonate is needed for later DNA synthesis to occur, nor reflect the pattern of cholesterol synthesis within the cells.