Proteomics to display lovastatin-induced protein and pathway regulation inrat liver

Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-me thylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cho lesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was anal yzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were fou nd to be significantly altered (p < 0.001) in relation to treatment. The ch anged proteins were classified according to their cellular function and par ticipation in biochemical pathways. The following observations were made: ( i) inhibition of HMG-CoA reductase provoked a regulatory response in the ch olesterol synthesis pathway including the induction of cytosolic HMG-CoA sy nthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydr ate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium hom eostasis, protease inhibition, cell signaling or apoptosis. These results p resent new insights into liver gene network regulations induced by lovastat in and illustrate a yet unexplored application of proteomics to discover ne w targets by analysis of existing drugs and the pathways that they regulate .