Basal laminar deposit formation in APO B100 transgenic mice: complex interactions between dietary fat, blue light, and vitamin E.
PURPOSE: Dietary fat intake has been proposed as a mechanism of sub-RPE deposit formation. It has been demonstrated recently that sub-RPE deposits develop in 16- to 18-month-old C57BL/6 mice fed a high-fat diet and exposed to blue-green light. Hyperlipidemia also develops in these mice after they consume a high-fat diet. Because hyperlipidemia also develops in young C57BL/6 mice that overexpress APO B100, the major apolipoprotein in LDL cholesterol, this research was conducted to determine whether high-fat diet and plasma hyperlipidemia correlate with formation of basal laminar deposits (BLD) in young transgenic mice. METHODS: APO B100 and wild-type C57BL/6 2-month-old mice were fed a high-fat diet for 4.5 months. After the first month, the right eyes were exposed to seven 5-second doses of nonphototoxic levels of blue-green light (20 mJ of argon 488 nm) over 2 weeks. Three months later, transmission electron microscopy (TEM) of the retina was performed to evaluate whether sub-RPE deposits correlate with plasma cholesterol and triglyceride levels. Several eyes were stained with filipin to detect cholesterol and osmium-thiocarbohydrazide-osmium (OTO) to detect neutral lipids in Bruch's membrane (BrM). A third group of APO B100 2-month-old mice were pretreated with vitamin E subcutaneously twice a week throughout the experiment and underwent the same light-exposure protocol. RESULTS: Mice fed a high-fat diet had a more elevated plasma triglyceride and cholesterol level than those that consumed a regular diet. Young APO B100 mice fed a high-fat diet had blood lipid levels higher than those in young wild-type mice that consumed high-fat diets, and these two groups had higher lipid levels than animals with regular diets, as shown previously in wild-type C57BL/6 (old and young). Eyes of APO B100 mice treated with blue-green light showed a high frequency of "moderate BLD", whereas the nonexposed eyes did not. In contrast, no BLD formed in either eye of the wild-type young mice fed a high-fat diet. In individual affected mice, only a weak correlation was observed between deposit severity and plasma lipid concentration. None of the eyes in mice with sustained hyperlipidemia with or without BLD demonstrated obvious widespread neutral lipid or cholesterol deposition in BLD or BrM. However, vitamin E-treated mice showed minimal formation of BLD. CONCLUSIONS: Although a high-fat diet is a necessary precondition for this model of BLD, the findings demonstrated a convincing direct correlation between plasma lipidemia and deposit severity. The results suggest that age, as shown in previous studies, and high-fat predispose to formation of BLD by altering hepatic and/or RPE lipid metabolism in ways more complicated than plasma hyperlipidemia alone.
Espinosa-Heidmann, DG; Sall, J; Hernandez, EP; Cousins, SW
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