Retinal and nonocular abnormalities in Cyp27a1(-/-)Cyp46a1(-/-) mice with dysfunctional metabolism of cholesterol
| Autor: | Casey D. Charvet, Timothy S. Kern, Aicha Saadane, Saida Omarova, Wenchao Zheng, Natalia Mast, Irina A. Pikuleva, Neal S. Peachey, Suber S. Huang |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Knockout Biology medicine.disease_cause Inbred C57BL Eye Medical and Health Sciences Retina Pathology and Forensic Medicine chemistry.chemical_compound Mice Internal medicine CYP27A1 medicine Pathology Cholesterol 24-Hydroxylase 2.1 Biological and endogenous factors Animals Cholesterol 24-hydroxylase Aetiology Liver X receptor Eye Disease and Disorders of Vision Lung Mice Knockout Retinal pigment epithelium Cholesterol Reverse Transcriptase Polymerase Chain Reaction Neurosciences Retinal Regular Article Mice Inbred C57BL Endocrinology medicine.anatomical_structure chemistry Biochemistry Liver Steroid Hydroxylases Cholestanetriol 26-Monooxygenase sense organs Oxidative stress Spleen |
| Zdroj: | The American journal of pathology, vol 184, iss 9 |
| ISSN: | 1525-2191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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