FARNESOL IS NOT THE NONSTEROL REGULATOR MEDIATING DEGRADATION OF HMG-COA REDUCTASE IN RAT-LIVER

A recent report, in which cultured tumor cells were used, identified f arnesol as the nonsterol mevalonate derived metabolite required for th e accelerated degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HM G-CoA) reductase (C. C. Correll, L. Ng, and P. A. Edwards, 1994, J. Bi ol. Chem. 269, 17390-17393). We examined this proposed linkage in anim als by measuring hepatic farnesol levels and rates of HMG-CoA reductas e degradation under conditions previously shown to alter the stability of the reductase. In normal rats, the hepatic farnesol level, quantif ied by high-pressure liquid chromatography, was 0.10 +/- 0.08 mu g/g a nd the half-life of HMG-CoA reductase was 2.5 h. Administration of mev alonolactone at 1 g/kg body wt to provide all nonsterol metabolites in addition to cholesterol increased farnesol levels 6-fold without sign ificantly affecting the half-life of the reductase, Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, raised hepat ic farnesol levels 10-fold and decreased the half-life of HMG-CoA redu ctase to 0.25 h, However, feeding lovastatin to rats did not lower hep atic farnesol levels despite a marked stabilization of HMG-CoA reducta se protein. Moreover, intubation of rats with 500 mg/kg body wt of far nesol failed to decrease the half-life of HMG-CoA reductase protein, a lter the levels of enzyme activity, or change of the levels of immunor eactive protein despite an increase of 1000 fold in hepatic farnesol l evels. These observations indicate that farnesol per se does not induc e accelerated degradation of HMG-CoA reductase in rat liver. (C) 1996 Academic Press, Inc.