Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element–Binding Protein-2

BACKGROUND—The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) appear to favorably influence the atherosclerotic process by different mechanisms. The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels. METHODS AND RESULTS—Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells. Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway. Simvastatin increased nuclear factors, notably sterol regulatory element–binding protein-2, capable of binding to the paraoxonase promoter; this was also blocked by mevalonate. Sterol regulatory element–binding protein-2 upregulated promoter activity in vitro. Patients treated with statin showed a significant increase in serum concentrations and activities of paraoxonase. CONCLUSIONS—The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity. It is consistent with effects of simvastatin treatment, which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level. The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated.