Abstract
Purpose: :
Cholesterol-metabolizing cytochromes P450 (CYP) 46A1 and 27A1 play key roles in extraocular cholesterol homeostasis. CYP46A1 initiates the major pathway of cholesterol elimination in the brain, and contributes to cognitive function. Ubiquitously expressed CYP27A1 is important for cholesterol removal from extrahepatic tissues, and complements HDL-mediated reverse cholesterol transport. Lack of CYP27A1 activity in humans results in the disease cerebrotendinous xanthomatosis (CTX), which is characterized by a constellation of symptoms, including neurologic abnormalities and premature atherosclerosis.Both enzymes are present in the retina, but their role in ocular function is not yet clear. A polymorphism in the CYP46A1 gene is associated with open-angle glaucoma. Patients with CTX develop premature cataracts and drusen as well as retinal pigmented epithelium changes. The purpose of this work is to characterize the visual function of mice deficient in either CYP27A1 or CYP46A1 (CYP27A1 KO and CYP46A1 KO). This will direct future studies exploring retinal cholesterol metabolism, and the potential role of disrupted cholesterol homeostasis in age-related eye disease.
Methods: :
Visual function in CYP46A1 and CYP27A1 KO mice was evaluated by electroretinograms (ERGs), and retinal morphology was evaluated with optical coherence tomography (OCT), and histochemistry.
Results: :
Compared to WT siblings, no significant changes in KO mouse ERG responses were observed until the age of 12 weeks. At 12 weeks the CYP27A1 KO mice showed statistically significant decreases in ERG b-wave amplitude. Conversely, CYP46A1 KO mice demonstrated an increase in b-wave amplitude, but these changes were not statistically significant. No significant morphological differences were observed in OCT images of retinal cross sections at 12 weeks in either KO type as compared to WT.
Conclusions: :
As in humans, CYPs 27A1 and 46A1 may play a role in ocular function in mice. Ongoing evaluation at 6 and 12 months will elucidate the nature of this role.
Keywords: age-related macular degeneration • lipids • retina