Abstract
Purpose: :
A correlation between the use of statins and a protection from age–related macular degeneration (AMD) is currently in debate, since some clinical studies show a positive correlation and other studies do not. The underlying molecular mechanism of such protective effect remains unknown. Here we are proposing a molecular mechanism which could also explain inconsistencies in clinical studies. Statins are a family of molecules that inhibit the synthesis of cholesterol and thus decrease the membrane content of cholesterol in cells. As a consequence, the membrane–bound transcription factor sterol regulatory element–binding protein–2 (SREBP–2) is activated by cleavage, allowing release and nuclear translocation of the active form. Nuclear SREBP–2 activates target genes such as HMGCoA synthase and the retinol dehydrogenase rdh11. In this study, we wanted to investigate if this pathway was taking place in mouse retina, as well as in the liver where it was first described.
Methods: :
Wild type mice were fed a diet containing 0, 0.05, 0.1, or 0.25% (w/w) lovastatin for up to 3 weeks and the liver and retinas were collected to quantify induction of rdh11 and HMGCoA synthase. mRNA levels were investigated by quantitative RT–PCR, protein expression by immunoblot, and immunofluorescence by confocal microscopy.
Results: :
As predicted, SREBP–2 target genes rdh11 and HMGCoA synthase are significantly induced in the liver by administration of lovastatin. These genes are induced in the retina in a dose– and time–dependent manner, suggesting an activation of SREBP–2. mRNA levels are induced 5– to 10–fold, and protein levels more than 3–fold. Immunofluorescence experiments reveal that lovastatin induction of rdh11 takes place in rod photoreceptor cells.
Conclusions: :
This study suggests a new basis to interpret the protection from AMD by statins, as a consequence of an induction of SREBP–2 and its target genes. Some of these genes might have retinal protective functions, as proposed for rdh11. Statins may be beneficial only for a specific population of AMD patients, depending on their genetic background.
Keywords: transcription factors • gene/expression • protective mechanisms