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Acceleration of Age-Related Changes in the Retina in -Tocopherol Transfer Protein Null Mice Fed a Vitamin E–Deficient Diet

¹From the Department of Ophthalmology, Shimane University School of Medicine, Shimane, Japan; ²Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Osaka, Japan; and ³Fujigotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan.

PURPOSE. To assess the role of vitamin E (VE) in age-related changes in the retinal tissues by using a mouse model of severe VE deficiency.

METHODS. Pups of -tocopherol transfer protein null (a-TTP^–/–) mice were fed a VE-deficient diet for 4 or 18 months (VE (–) group). Wild-type C57BL/6 mice were fed a 0.002% -tocopherol–supplemented diet (VE (+) group). In various ocular tissues, the VE levels were measured by high-performance liquid chromatography; the fatty acid composition by gas chromatography (GC); and the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F₂ levels, which are biomarkers for lipid peroxidation, by GC-mass spectrometry. The retinal structure was assessed by light, electron, and fluorescence microscopy.

RESULTS. The -tocopherol level in the retinas obtained from 4-month-old VE (–) animals was 71-fold lower than that in the retinas obtained from the VE (+) group. In addition, -tocopherol was not detected; thus, the VE (–) group demonstrated a more severe VE deficiency than ever reported. In this group, the concentration of n-3 polyunsaturated fatty acids decreased (0.3- to 0.9-fold), whereas that of other classes of fatty acids was unchanged or increased. At 18 months of age, the number of the outer nuclear layer (ONL) nuclei was observed to be 17% lower in the VE (–) than in the VE (+) group (P < 0.05). Electron microscopy revealed larger amounts of matrix between the ONL nuclei indicating the Müller cell hypertrophy, greatly expanded rod outer segment discs, and a larger number of inclusion bodies in the retinal pigment epithelium (RPE; P < 0.05) in the VE (–) group. Fluorescence microscopy revealed that the autofluorescence signal was increased in the RPE layer in this group. When the observations of the 18-month-old animals were compared to those of the 4-month-old animals, the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F₂ levels were found to be increased in the retina and RPE obtained from both the VE (–) and VE (+) groups; however, the age-related increases were more remarkable in the VE (–) group (2.6- to 43.5-fold) than in the VE (+) group (0.8- to 8.7-fold).

CONCLUSIONS. The combined use of a-TTP^–/– mice and a VE-deficient diet leads to a severe deficiency of VE, enhances lipid peroxidation in the retina, and accelerates degenerative damage of the retina with age.