Short- and long-term effects of atorvastatin, lovastatin and simvastatin on the cellular metabolism of cholesteryl esters and VLDL secretion in rat hepatocytes

The short- and long-term in vitro effects of the hydroxymethylglutaryl-CoA reductase inhibitor atorvastatin, compared with lovastatin and simvastatin on VLDL secretion, and on the formation and the neutral and acid lysosomal hydrolysis of cholesteryl esters was investigated in rat liver hepatocytes maintained in suspension (2 or 4 h) or cultured in monolayers (24 h). All s tatins time-dependently reduced [C-14]oleate incorporation into cholesteryl esters, but when exogenous cholesterol was added only atorvastatin caused an immediate transient decrease in hepatocyte ACAT activity. Activity of th e lysosomal, microsomal and cytosolic CEH isoforms was unaffected by the he patocyte treatments. Statins reduced free and esterified cholesterol mass i n hepatocyte microsomes after 2 h, and this was followed by a modest declin e in VLDL cholesteryl esters, whilst secretion of VLDL apoB and triglycerid es was unaltered. However, after 24 h of treatment, statins caused generali zed 20-40% decreases in the secretion of VLDL apoB, cholesterol and triglyc erides, with the reduction in apoB48 secretion being significantly superior to that caused in apoB100. The mean diameter of secreted VLDL was not modi fied by either duration or drug treatment. Additional studies with subcellu lar fractions demonstrated that statins have a direct selective effect on t he enzymes governing the cholesterol-cholesteryl eater cycle, with the exce ption of the microsomal CEH. Atorvastatin, lovastatin and simvastatin inhib ited ACAT activity in microsomes by 50% at doses of 250, 100 and 50 muM, re spectively. The cytosolic CEH elicited a biphasic profile of activity with activations up to 100 muM statin and inhibitions above 250 muM, and the lys osomal CEH was only inhibited by atorvastatin at a dose of 100 muM or more. We conclude that a prolonged, but not a short, limited availability of hep atocyte cholesterol derived from the endogenous synthesis reduces VLDL secr etion, and that reactivity of statins at the cellular level are more simila r than reactivity at the subcellular level as regards the cholesterol-chole steryl ester cycle. (C) 2000 Elsevier Science Ireland Ltd. All rights reser ved.