TY - JOUR T1 - Retinal Cholesterol Content is Reduced in Simvastatin-Treated Mice Due to Inhibited Local Biosynthesis Albeit Increased Uptake of Serum Cholesterol JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.083345 SP - dmd.118.083345 AU - Natalia Mast AU - Ilya R. Bederman AU - Irina A. Pikuleva Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/08/16/dmd.118.083345.abstract N2 - Statins, a class of cholesterol-lowering drugs, are currently investigated for treatment of age-related macular degeneration, a retinal disease. Herein, retinal and serum concentrations of four statins (atorvastatin, simvastatin, pravastatin, and rosuvastatin) were evaluated after mice were given a single drug dose of 60 mg/kg body weight. All statins, except rosuvastatin, were detected in the retina: atorvastatin and pravastatin at 1.6 pmols and simvastatin at 4.1 pmols. Serum statin concentrations (pmol/ml) were 223 (simvastatin), 1,401 (atorvastatin), 2,792 (pravastatin), and 9,050 (rosuvastatin). Simvastatin was then administered to mice daily for 6 weeks at 60 mg/kg of body weight dose. Simvastatin treatment reduced serum cholesterol levels by 18% and retinal content of cholesterol, lathosterol but not desmosterol by 24% and 21%, respectively. The relative contributions of retinal cholesterol biosynthesis and retinal uptake of serum cholesterol to total retinal cholesterol input were changed as well. These contributions were 79% and 21%, respectively, in vehicle-treated mice and 69% and 31%, respectively, in simvastatin-treated mice. Thus, simvastatin treatment lowered retinal cholesterol because a compensatory upregulation of retinal uptake of serum cholesterol was not sufficient to overcome the effect of inhibited retinal biosynthesis. Simultaneously, simvastatin-treated mice had a 2.9-fold increase in retinal expression of Cd36, the major receptor clearing oxidized low-density lipoproteins from Bruch's membrane. Notably, simvastatin treatment essentially did not affect brain cholesterol homeostasis. Our results reveal the statin effect on the retinal and brain cholesterol input and are of value for future clinical investigations of statins as potential therapeutics for age-related macular degeneration. ER -