Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells

We evaluated the effects of the hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGRI) atorvastatin, lovastatin, and simvastatin on lipid homeo stasis in HepG2 cells. The drugs were almost equally effective in inhibitin g cholesterol synthesis and in decreasing cellular cholesterol. Atorvastati n and lovastatin increased low-density lipoprotein receptor mR_NA (2.5-fold at 3 x 10(-7) M) and the transcription rate at the promoter of the low-den sity lipoprotein receptor gene (>5-fold at 10(-6) M). The three compounds e nhanced the activity of the low-density lipoprotein receptor at a similar m agnitude (1.6-2.1-fold at 10(-6) M). Atorvastatin and lovastatin increased the nuclear form of sterol regulatory element binding protein (SREBP)-2, bu t not of SREBP-1. Each of the drugs increased triacylglyceride synthesis (5 0% 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 cont aining particles by similar to 50% and increased the ratio of triacylglycer ides to apo B by similar to 35%. We conclude that regulatory responses to H MGRI 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 profoun dly alter their composition, and that atorvastatin does not significantly d iffer from other HMGRI in these regards. (C) 2001 Elsevier Science Inc. All rights reserved.