Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apoB-100 and triglyceride secretion from HepG2 cells

Atorvastatin is a new HMG-CoA reductase inhibitor that strongly lowers plas ma cholesterol and triglyceride (TG) levels in humans and animals. Since pr evious data indicated that atorvastatin has prolonged inhibition of hepatic cholesterol synthesis, we tested whether this longer duration of inhibitor y effect on cholesterol synthesis decreased hepatic lipoprotein secretion i n vitro. We used the HepG2 hepatoma cell line to: (1) determine the time re quired Lentil levels of secreted apo B-100 and TG declined significantly, ( 2) examine the relation to the mass of cellular cholesteryl ester (CE) and (3) test microsomal triglyceride transfer protein (MTP) activity which lead s to decreased apo B-100 production. Although atorvastatin significantly in hibited cholesterol synthesis in,HepG2 cells regardless of treatment durati on (1, 14 or 24 h). it did not inhibit TG synthesis. Apo B-100 and TG secre tion were unchanged after 1-h atorvastatin treatment, but declined signific antly after 24-h treatment. Atorvastatin treatment also reduced cellular CE mass, exhibiting both time- and dose-dependency. Mevalonolactone, a produc t of HMG-CoA reductase, attenuated the inhibitory effects of atorvastatin. Atorvastatin strongly reduced mRNA levels of MTP, whereas it did not inhibi t MTP activity as measured by TG transfer assay between liposomes. Simvasta tin also induced treatment- and time-dependent reductions in apo B-100. whe reas the MTP inhibitor BMS-201038 exhibited no time dependency, instead inh ibiting this variable even on I-h treatment. These results: indicate that r educed apo B-100 secretion caused by atorvastatin is: a secondary result ow ing to decreased lipid availability, and that atorvastatin's: efficacy depe nds on the duration of cholesterol synthesis inhibition in the liver. (C) 2 001 Elsevier Science Ireland Ltd. All rights reserved.