Retinal Cholesterol Content Is Reduced in Simvastatin-Treated Mice Due to Inhibited Local Biosynthesis Albeit Increased Uptake of Serum Cholesterol

Abstract

Statins, a class of cholesterol-lowering drugs, are currently being 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 pmol and simvastatin at 4.1 pmol. Serum statin concentrations (pmol/ml) were 223 (simvastatin), 1401 (atorvastatin), 2792 (pravastatin), and 9050 (rosuvastatin). Simvastatin was then administered to mice daily for 6 weeks at 60 mg/kg body weight. Simvastatin treatment reduced serum cholesterol levels by 18% and retinal content of cholesterol and 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 , 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.

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

“…7f). Also as reported 30,31 , statin induced a reduction of circulating cholesterol. However, such reduction was not affected by the antagonist (Fig.…”

Mechanisms that minimize retinal impact of apolipoprotein E absence

“…In the serum, total lathosterol is an indicator of cholesterol biosynthesis in whole body (46), and total 24-hydroxycholesterol is a marker of cholesterol elimination from the brain (47). In the retina, lathosterol reflects cholesterol biosynthesis in neurons (48,49), and desmosterol could be a marker of cholesterol biosynthesis in astrocytes (3). The 24-hydroxycholesterol and 5-cholestenoic acid indicate retinal cholesterol elimination by metabolism, which along with cholesterol removal by LPP is an important contributor to retinal cholesterol maintenance (4,37,50,51).…”

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

“…54 days) in the retina, and the estimated contribution of endogenous (retina-derived) biosynthesis to the total retinal cholesterol pool (ca. 72%) (59), it was concluded that systemic simvastatin treatment led to partial inhibition of retinal HMGCR activity (60,61). This further verifies the local activity of the mevalonate pathway in the retina.…”

“…Intravitreal injection of lovastatin led to early changes in the structural organization of the neural retina characterized by formation of rosette-like arrangements of photoreceptors, and eventually necrosis of the retina by 4 days (48,49). However, contrary to initial expectations, such effects of lovastatin were found to be due to defective protein prenylation in the retina, rather than to disruption of cholesterol synthesis (54 Systemically administered simvastatin was shown to exhibit the highest bioavailability compared to other statins (after 6 weeks) in the neural retina of mice (60), and also was significantly higher compared to brain tissue, suggesting that simvastatin is permeable to the blood-retinal barrier.…”