We evaluated the effects of the hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGRI) atorvastatin, lovastatin, and simvastatin on lipid homeostasis in HepG2 cells. The drugs were almost equally effective in inhibiting cholesterol synthesis and in decreasing cellular cholesterol. Atorvastatin and lovastatin increased low-density lipoprotein receptor mRNA (2.5-fold at 3 x 10(-7) M) and the transcription rate at the promoter of the low-density lipoprotein receptor gene (>5-fold at 10(-6) M). The three compounds enhanced the activity of the low-density lipoprotein receptor at a similar magnitude (1.6-2.1- fold at 10(-6) M). Atorvastatin and lovastatin increased the nuclear form of sterol regulatory element binding protein (SREBP)-2, but not of SREBP-1. Each of the drugs increased triacylglyceride synthesis (50% at 10(-7)-10(-6) M), cellular triacylglyceride content (16% at 10(-6) M), and expression of fatty acid synthase by reporter gene and Northern blot analysis (2-fold and 2.7-fold at 10(-6) M and 3 x 10(-7) M, respectively). All compounds reduced the secretion of apo B (30% at 3 x 10(-7) M). HMGRI decreased the ratio of cholesterol to apo B in newly synthesised apo B containing particles by approximately 50% and increased the ratio of triacylglycerides to apo B by approximately 35%. We conclude that regulatory responses to HMGRI are mediated by SREBP-2 rather than by SREBP-1, that HMGRI oppositely affect the cellular cholesterol and triacylglyceride production, that HMGRI moderately decrease the release of apo B containing particles, but profoundly alter their composition, and that atorvastatin does not significantly differ from other HMGRI in these regards.