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Qi Wang, Svetlana N. bozack, Todd A. Lydic, Kelly M. Mcsorley, Matthew S. Faber, Maria Tikhonenko, Julia V. Busik; Dysregulation of Circadian Pattern of Lipid Metabolism in the Diabetic retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3591.
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We have previously demonstrated that down regulation of fatty acid elongases Elovl2 and 4 with concomitant changes in retinal fatty acid profiles play an important role in pathogenesis of diabetic retinopathy. Key transcription factors controlling fatty acid metabolism are known to be under circadian regulation and in turn were shown to affect the core clock mechanism in the liver, however, the link between metabolic regulatory genes and clock genes have never been established in the retina. The purpose of this study is to establish the relation between the circadian clock, fatty acid metabolic pathways, and the key transcription factors controlling fatty acid metabolism: SREBP-1c, PPARα, and PPARγ in the retina and to determine whether this regulatory mechanism is impaired in diabetes.
Type 1 diabetic (n=3) rats and age matched controls (n=3) were used. All rats were kept in standard 12/12 light/dark cycle conditions. Rats were sacrificed and their retinas were harvested for RNA and protein analysis every two hrs for a 24 hr period. The expression levels of clock genes (Clock, Bmal-1, Per-1, Per-2, Cry-1, Cry-2 and Erb) and lipid metabolic genes (PPARα, PPARγ, SREBP-1c, ELOVL4 and ELOVL2) were examined by quantitative real-time PCR. The protein levels of SREBP-1c, ELOVL4 and ELOVL2 were analyzed by western blot.
Clock, Bmal-1, Per-1, Per-2, Cry-1 and Cry-2 exhibited a circadian rhythm in the retina (p<0.05). Out of these genes circadian expression of Clock, Bmal-1, Per-1, and Per-2 was significantly affected by diabetes. Similar circadian rhythm of expression was also observed for lipid metabolic genes SREBP-1C and PPARα in retina (p<0.001). Lipid metabolic genes, SREBP-1C, PPARγand ELOVL2 also showed differential expression profiles in the diabetic versus control rats (p<0.01).
Our results demonstrate that the expression of lipid metabolic genes in the retina is under the regulation of circadian clock. Dysregulation of circadian clock in the diabetic retina leads to changes in light/dark pattern of retinal lipid metabolism, which has potential implications for the development of diabetic retinopathy.
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