Genetic tuning of β-carotene oxygenase-1 activity rescues cone photoreceptor function in STRA6-deficient mice
- 23 September 2022
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 32 (5), 798-809
- https://doi.org/10.1093/hmg/ddac242
Abstract
Rod and cone photoreceptors in the retina mediate dim light and daylight vision, respectively. Despite their distinctive functions, rod and cone visual pigments utilize the same vitamin A-derived chromophore. To sustain vision, vitamin A precursors must be acquired in the gut, metabolized, and distributed to the eyes. Deficiencies in this pathway in inherited ocular disease states deplete cone photoreceptors from chromophore and eventually lead to cell death, whereas the more abundant rod photoreceptors are less affected. However, pathways that support cone function and survival under such conditions are largely unknown. Using biochemical, histological, and physiological approaches, we herein show that intervention with β-carotene in STRA6-deficient mice improved chromophore supply to cone photoreceptors. Relieving the inherent negative feedback regulation of β-carotene oxygenase-1 activity in the intestine by genetic means further bolstered cone photoreceptor functioning in the STRA6-deficient eyes. A vitamin A-rich diet, however, did not improve cone photoreceptor function in STRA6-deficiency. We provide evidence that the beneficial effect of β-carotene on cones results from favorable serum kinetics of retinyl esters in lipoproteins. The respective alterations in lipoprotein metabolism maintained a steady supply of retinoids to the STRA6-deficient eyes, which ameliorated the competition for chromophore between rod and cone photoreceptors. Together, our study elucidates a cone photoreceptor-survival pathway and unravels an unexpected metabolic connection between the gut and the retina.Funding Information
- Light Microscopy Core Grant (1S10OD024981-01)
- T32 Visual Sciences Training Grant (EY007157)
- National Eye Institute (EY011373, EY028121)
This publication has 63 references indexed in Scilit:
- Genetics and Diet Regulate Vitamin A Production via the Homeobox Transcription Factor ISXOnline Journal of Public Health Informatics, 2013
- Genetic Determinants of Macular Pigments in Women of the Carotenoids in Age-Related Eye Disease StudyInvestigative Ophthalmology & Visual Science, 2013
- Retinoid Content, Visual Responses, and Ocular Morphology Are Compromised in the Retinas of Mice Lacking the Retinol-Binding Protein Receptor, STRA6Investigative Ophthalmology & Visual Science, 2012
- Uptake of Dietary Retinoids at the Maternal-Fetal Barrier: IN VIVO EVIDENCE FOR THE ROLE OF LIPOPROTEIN LIPASE AND ALTERNATIVE PATHWAYSOnline Journal of Public Health Informatics, 2011
- Dietary 9-cis-β,β-Carotene Fails to Rescue Vision in Mouse Models of Leber Congenital AmaurosisMolecular Pharmacology, 2011
- β-Carotene Is an Important Vitamin A Source for HumansJournal of Nutrition, 2010
- ISX is a retinoic acid‐sensitive gatekeeper that controls intestinal β,β‐carotene absorption and vitamin A productionThe FASEB Journal, 2010
- In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell deathHuman Molecular Genetics, 2009
- Retinopathy in Mice Induced by Disrupted All-trans-retinal ClearanceOnline Journal of Public Health Informatics, 2008
- Xanthophylls are preferentially taken up compared with β-carotene by retinal cells via a SRBI-dependent mechanism*Journal of Lipid Research, 2008