title: Retinal and nonocular abnormalities in Cyp27a1(-/-)Cyp46a1(-/-) mice with dysfunctional metabolism of cholesterol.
abstract: Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1(-/-)Cyp46a1(-/-) mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1(-/-)Cyp46a1(-/-) mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature.
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
authors: Aicha
authors: A
authors: Saadane
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
authors: Natalia
authors: N
authors: Mast
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
authors: Casey D
authors: CD
authors: Charvet
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
authors: Saida
authors: S
authors: Omarova
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio.
authors: Wenchao
authors: W
authors: Zheng
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors: Suber S
authors: SS
authors: Huang
authors: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors: Timothy S
authors: TS
authors: Kern
authors: Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Cleveland VA Medical Center, Cleveland, Ohio; Department of Medicine, University Hospitals, Cleveland, Ohio.
authors: Neal S
authors: NS
authors: Peachey
authors: Department of Ophthalmology and Visual Sciences, Cleveland, Ohio. Electronic address: iap8@case.edu.
authors: Irina A
authors: IA
authors: Pikuleva
mesh_terms: D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000172:deficiency*; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013250:Steroid Hydroxylases / Q000172:deficiency*
chemical_list: D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse