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All-Trans-Retinal

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Krzysztof Palczewski – One of the best experts on this subject based on the ideXlab platform.

  • Prolonged prevention of retinal degeneration with retinylamine loaded nanoparticles.
    Biomaterials, 2015
    Co-Authors: Anthony Puntel, Marcin Golczak, Akiko Maeda, Song Qi Gao, Krzysztof Palczewski
    Abstract:

    Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retiretinal). Inefficient clearance of toxic retinoid metabolites, especially All-Trans-Retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of All-Trans-Retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4(-/-)Rdh8(-/-) (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration.

  • Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration
    Molecular pharmacology, 2014
    Co-Authors: Jianye Zhang, Krzysztof Palczewski, Zhiqian Dong, Sreenivasa R. Mundla, William L. Seibel, Ruben Papoian, Marcin Golczak
    Abstract:

    All-Trans-Retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of All-Trans-Retinal by drugs containing a primary aminamine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retiretinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl esteester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

  • retinyl ester storage particles retinosomes from the retinal pigmented epithelium resemble lipid droplets in other tissues
    Journal of Biological Chemistry, 2011
    Co-Authors: Tivadar Orban, Grazyna Palczewska, Krzysztof Palczewski
    Abstract:

    Levels of many hydrophobic cellular substances are tightly regulated because of their potential cytotoxicity. These compounds tend to self-aggregate in cytoplasmic storage depots termed lipid droplets/bodies that have well defined structures that contain additional components, including cholesterol and various proteins. Hydrophobic substances in these structures become mobilized in a specific and regulated manner as dictated by cellular requirements. Retinal pigmented epithelial cells in the eye produce retinyl esteester-containing lipid droplets named retinosomes. These esters are mobilized to replenish the visual chromophore, 11-cis-retiretinal, and their storage ensures proper visual function despite fluctuations in dietary vitamin A intake. But it remains unclear whether retinosomes are structures specific to the eye or similar to lipid droplets in other organs/tissues that contain substances other than retinyl esters. Thus, we initially investigated the production of these lipid droplets in experimental cell lines expressing lecithin:retinol acyltransferase, a key enzyme involved in formation of retinyl esteester-containing retinosomes from all-trans-retinol. We found that retinosomes and oleate-derived lipid droplets form and co-localize concomitantly, indicating their intrinsic structural similarities. Next, we isolated native retinosomes from bovine retinal pigmented epithelium and found that their protein and hydrophobic small molecular constituents were similar to those of lipid droplets reported for other experimental cell lines and tissues. These unexpected findings suggest a common mechanism for lipid droplet formation that exhibits broad chemical specificity for the hydrophobic substances being stored.

Joseph L. Napoli – One of the best experts on this subject based on the ideXlab platform.

  • Multiple Retinol and Retinal Dehydrogenases Catalyze All-trans-retinoic Acid Biosynthesis in Astrocytes
    The Journal of biological chemistry, 2010
    Co-Authors: Chao Wang, Maureen A. Kane, Joseph L. Napoli
    Abstract:

    All-trans-retinoic acid (atRA) stimulates neurogenesis, dendritic growth of hippocampal neurons, and higher cognitive functions, such as spatial learning and memory formation. Although astrocyte-derived atRA has been considered a key factor in neurogenesis, little direct evidence identifies hippocampus cell types and the enzymes that biosynthesize atRA. Here we show that primary rat astrocytes, but not neurons, biosynthesize atRA using multiple retinol dehydrogenases (Rdh) of the short chain dehydrogenase/reductase gene family and retinaldehyde dehydrogenases (Raldh). Astrocytes secrete atRA into their medium; neurons sequester atRA. The first step, conversion of retinol into retinal, is rate-limiting. Neurons and astrocytes both synthesize retinyl esters and reduce retinal into retinol. siRNA knockdown indicates that Rdh10, Rdh2 (mRdh1), and Raldh1, -2, and -3 contribute to atRA production. Knockdown of the Rdh Dhrs9 increased atRA synthesis ∼40% by increasing Raldh1 expression. Immunocytochemistry revealed cytosolic and nuclear expression of Raldh1 and cytosol and perinuclear expression of Raldh2. atRA autoregulated its concentrations by inducing retinyl esteester synthesis via lecithin:retinol acyltransferase and stimulating its catabolism via inducing Cyp26B1. These data show that adult hippocampus astrocytes rely on multiple Rdh and Raldh to provide a paracrine source of atRA to neurons, and atRA regulates its own biosynthesis in astrocytes by directing flux of retinol. Observation of cross-talk between Dhrs9 and Raldh1 provides a novel mechanism of regulating atRA biosynthesis.

  • reduction of all trans retinal in the mouse liver peroxisome fraction by the short chain dehydrogenase reductase rrd induction by the ppar alpha ligand clofibrate
    Biochemistry, 2003
    Co-Authors: Zhen Lei, Weiguo Chen, Min Zhang, Joseph L. Napoli
    Abstract:

    The mouse liver 16,000 g fraction, which contains peroxisomes, reduces All-Trans-Retinal, but has limited ability to dehydrogenate retinol enzymatically. Feeding mice for 2 weeks with a diet containing clofibrate (0.5%, w/w), a PPAR alpha ligand and peroxisome proliferator, increased the 16,000 g fraction approximately 2-fold in protein, approximately 2-fold in specific activity of retinal reduction, and approximately 4-fold in retinal reductase units compared to controls, and caused a 50% decrease in liver retinol. An increase in both reductase specific activity and units indicates that clofibrate/PPAR alpha induced expression of retinal-reducing enzymes(s), in addition to increasing reductase(s) content. We expressed a cDNA from the NCBI data bank that encodes a peroxisome short-chain dehydrogenase/reductase. The enzyme, mouse retinal reductase (RRD, also known as human 2,4-dienoyl-CoA reductase), reduces All-Trans-Retinal [V(m) = 40 nmol min(-1) (mg of protein)(-1); K(0.5) = 2.3 microM] and has 4- and 60-fold less activity with 13-cis-retinal and 9-cis-retinal, respectively. Recombinant RRD functions with both unbound and CRBP(I) (cellular retinol-binding protprotein)-bound retinal, but apo-CRBP(I) inhibits the reductase. RRD mRNA expression was initiated on embryo day 7. Most adult tissues assayed expressed the mRNA. Liver, kidney, and heart had the most intense expression, with much less intense expression in brain, spleen, and lung. Clofibrate feeding increased the amount of RRD protein in the 16,000 g fraction of liver, consistent with the clofibrate-induced increase in reductase activity. These data relate retinoid metabolism, PPAR alpha, peroxisomes, and RRD, and are consistent with a further function of CRBP(I) in retinoid metabolism.

  • Reduction of All-Trans-Retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPAR alpha ligand clofibrate.
    Biochemistry, 2003
    Co-Authors: Zhen Lei, Weiguo Chen, Min Zhang, Joseph L. Napoli
    Abstract:

    The mouse liver 16,000 g fraction, which contains peroxisomes, reduces All-Trans-Retinal, but has limited ability to dehydrogenate retinol enzymatically. Feeding mice for 2 weeks with a diet containing clofibrate (0.5%, w/w), a PPAR alpha ligand and peroxisome proliferator, increased the 16,000 g fraction approximately 2-fold in protein, approximately 2-fold in specific activity of retinal reduction, and approximately 4-fold in retinal reductase units compared to controls, and caused a 50% decrease in liver retinol. An increase in both reductase specific activity and units indicates that clofibrate/PPAR alpha induced expression of retinal-reducing enzymes(s), in addition to increasing reductase(s) content. We expressed a cDNA from the NCBI data bank that encodes a peroxisome short-chain dehydrogenase/reductase. The enzyme, mouse retinal reductase (RRD, also known as human 2,4-dienoyl-CoA reductase), reduces All-Trans-Retinal [V(m) = 40 nmol min(-1) (mg of protein)(-1); K(0.5) = 2.3 microM] and has 4- and 60-fold less activity with 13-cis-retinal and 9-cis-retinal, respectively. Recombinant RRD functions with both unbound and CRBP(I) (cellular retinol-binding protprotein)-bound retinal, but apo-CRBP(I) inhibits the reductase. RRD mRNA expression was initiated on embryo day 7. Most adult tissues assayed expressed the mRNA. Liver, kidney, and heart had the most intense expression, with much less intense expression in brain, spleen, and lung. Clofibrate feeding increased the amount of RRD protein in the 16,000 g fraction of liver, consistent with the clofibrate-induced increase in reductase activity. These data relate retinoid metabolism, PPAR alpha, peroxisomes, and RRD, and are consistent with a further function of CRBP(I) in retinoid metabolism.

Yiannis Koutalos – One of the best experts on this subject based on the ideXlab platform.

  • Photooxidation mediated by 11-cis and all-trans retinal in single isolated mouse rod photoreceptors
    Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology, 2020
    Co-Authors: Chunhe Chen, Masahiro Kono, Yiannis Koutalos
    Abstract:

    Retinal, the vitamin A aldehyde, is a potent photosensitizer that plays a major role in light-induced damage to vertebrate photoreceptors. 11-Cis retinal is the light-sensitive chromophore of rhodopsin, the photopigment of vertebrate rod photoreceptors. It is isomerized by light to all-trans, activating rhodopsin and beginning the process of light detection. All-trans retinal is released by activated rhodopsin, allowing its regeneration by fresh 11-cis retinal continually supplied to photoreceptors. The released all-trans retinal is reduced to all-trans retinol in a reaction using NADPH. We have examined the photooxidation mediated by 11-cis and all-trans retinal in single living rod photoreceptors isolated from mouse retinas. Photooxidation was measured with fluorescence imaging from the oxidation of internalized BODIPY C11, a fluorescent dye whose fluorescence changes upon oxidation. We found that photooxidation increased with the concentration of exogenously added 11-cis or all-trans retinal to metabolically compromised rod outer segments that lacked NADPH supply. In dark-adapted metabolically intact rod outer segments with access to NADPH, there was no significant increase in photooxidation following exposure of the cell to light, but there was significant increase following addition of exogenous 11-cis retinal. The results indicate that both 11-cis and all-trans retinal can mediate light-induced damage in rod photoreceptors. In metabolically intact cells, the removal of the all-trans retinal generated by light through its reduction to retinol minimizes all-trans retinal-mediated photooxidation. However, because the enzymatic machinery of the rod outer segment cannot remove 11-cis retinal, 11-cis-retiretinal-mediated photooxidation may play a significant role in light-induced damage to photoreceptor cells.

  • RPE65 and the Accumulation of Retinyl Esters in Mouse Retinal Pigment Epithelium
    Photochemistry and Photobiology, 2017
    Co-Authors: Colleen Sheridan, Rosalie K. Crouch, Nicholas P. Boyer, Yiannis Koutalos
    Abstract:

    The RPE65 protein of the retinal pigment epithelium (RPE) enables the conversion of retinyl esters to the visual pigment chromophore 11-cis retinal. Fresh 11-cis retinal is generated from retinyl esters following photoisomerization of the visual pigment chromophore to all-trans during light detection. Large amounts of esters accumulate in Rpe65-/- mice, indicating their continuous formation when 11-cis retinal generation is blocked. We hypothesized that absence of light, by limiting the conversion of esters to 11-cis retinal, would also result in the build-up of retinyl esters in the RPE of wild-type mice. We used HPLC to quantify ester levels in organic extracts of the RPE from wild-type and Rpe65-/- mice. Retinyl esteester levels in Sv/129 wild-type mice that were dark adapted for various intervals over a 4-week period were similar to those in mice raised in cyclic light. In C57BL/6 mice however, which contain less Rpe65 protein, dark adaptation was accompanied by an increase in ester levels compared to cyclic light controls. Retinyl esteester levels were much higher in Rpe65-/- mice compared to wild type and kept increasing with age. The results suggest that the RPE65 role in retinyl esteester homeostasis extends beyond enabling the formation of 11-cis retinal.

  • All-trans retinal levels and formation of lipofuscin precursors after bleaching in rod photoreceptors from wild type and Abca4-/- mice
    Experimental eye research, 2017
    Co-Authors: Leopold Adler, Chunhe Chen, Yiannis Koutalos
    Abstract:

    The accumulation of lipofuscin in the cells of the retinal pigment epithelium (RPE) is thought to play an important role in the development and progression of degenerative diseases of the retina. The bulk of RPE lipofuscin originates in reactions of the rhodopsin chromophore, retinal, with components of the photoreceptor outer segment. The 11-cis retinal isomer is generated in the RPE and supplied to rod photoreceptor outer segments where it is incorporated as the chromophore of rhodopsin. It is photoisomerized during light detection to all-trans and subsequently released by photoactivated rhodopsin as all-trans retinal, which is removed through reduction to all-trans retinol in a reaction requiring metabolic input in the form of NADPH. Both 11-cis and all-trans retinal can form lipofuscin precursor fluorophores in rod photoreceptor outer segments. Increased accumulation of lipofuscin has been suggested to result from excess formation of lipofuscin precursors due to buildup of all-trans retinal released by light exposure. In connection with this suggestion, the Abca4 transporter protprotein, an outer segment protein defects in which result in recessive Stargardt disease, has been proposed to promote the removal of all-trans retinal by facilitating its availability for reduction. To examine this possibility, we have measured the outer segment levels of all-trans retinal, all-trans retinol, and of lipofuscin precursors after bleaching by imaging the fluorescence of single rod photoreceptors isolated from wild type and Abca4-/- mice. We found that all-trans retinol and all-trans retinal levels increased after bleaching in both wild type and Abca4-/- rods. At all times after bleaching, there was no significant difference in all-trans retinal levels between the two strains. All-trans retinol levels were not significantly different between the two strains at early times, but were lower in Abca4-/- rods at times longer than 20 min after bleaching. Bleaching in the presence of lower metabolic substrate concentrations resulted in higher all-trans retinal levels and increased formation of lipofuscin precursors in both wild type and Abca4-/- rods. The results show that conditions that result in buildup of all-trans retinal levels result in increased generation of lipofuscin precursors in both wild type and Abca4-/- rods. The results are consistent with the proposal that Abca4 facilitates the reduction of all-trans retinal to retinol; absence of Abca4 however does not appear to be associated with higher all-trans retinal levels compared to wild type.

Akiko Maeda – One of the best experts on this subject based on the ideXlab platform.

  • RPE Visual Cycle and Biochemical Phenotypes of Mutant Mouse Models.
    Methods in Molecular Biology, 2018
    Co-Authors: Bhubanananda Sahu, Akiko Maeda
    Abstract:

    The retinal pigmented epithelium (RPE) is a single layer of polarized epithelial cells which plays many important roles for visual function. One of such roles is production of visual chromophore, 11-cis-retiretinal through the visual cycle. The visual cycle consists of biochemical processes for regenerating chromophore by a collective action of the RPE and photoreceptor. Photoreceptors harbor the G protprotein-coupled receptors, opsin which enables to receive light when it bounds to 11-cis-retiretinal. With absorption of a photon of light, 11-cis-retiretinal photoisomerizes to All-Trans-Retinal. All-Trans-Retinal reduces to all-trans-retinol in the photoreceptor and further recycles back to 11-cis-retiretinal in the RPE. Acyltransferases and isomerohydrolase(s) along with retinol dehydrogenases sequentially convert all-trans-retinol to 11-cis-retiretinal in the RPE. Dysfunctions of any retinoid cycle enzymes in the RPE can cause retinal diseases. Phenotyping RPE functions by the use of mutant mouse models will provide great detailed biochemical insights of the visual cycle and further manipulative strategies to protect against retinal degeneration. Here, we describe biochemical analyses of the visual cycle in mouse models using RPE cells.

  • Prolonged prevention of retinal degeneration with retinylamine loaded nanoparticles.
    Biomaterials, 2015
    Co-Authors: Anthony Puntel, Marcin Golczak, Akiko Maeda, Song Qi Gao, Krzysztof Palczewski
    Abstract:

    Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially All-Trans-Retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of All-Trans-Retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4(-/-)Rdh8(-/-) (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration.

  • autophagy protects the retina from light induced degeneration
    Journal of Biological Chemistry, 2013
    Co-Authors: Yu Chen, Tadao Maeda, Osamu Sawada, Hideo Kohno, Carlos S Subauste, Akiko Maeda
    Abstract:

    Autophagy is a conserved feature of lysosome-mediated intracellular degradation. Dysregulated autophagy is implicated as a contributor in neurodegenerative diseases; however, the role of autophagy in retinal degeneration remains largely unknown. Here, we report that the photo-activated visual chromophore, All-Trans-Retinal, modulated autophagosome formation in ARPE19 retinal cells. Increased formation of autophagosomes in these cells was observed when incubated with 2.5 μm All-Trans-Retinal, a condition that did not cause cell death after 24 h in culture. However, autophagosome formation was decreased at concentrations, which caused cell death. Increased expression of activating transcription factor 4 (Atf4), which indicates the activation of oxidative stress, was recorded in response to light illumination in retinas of Abca4−/−Rdh8−/− mice, which showed delayed clearance of All-Trans-Retinal after light exposure. Expression of autophagosome marker LC3B-II and mitochondria-specific autophagy, mitophagy, regulator Park2, were significantly increased in the retinas of Abca4−/−Rdh8−/− mice after light exposure, suggesting involvement of autophagy and mitophagy in the pathogenesis of light-induced retinal degeneration. Deletion of essential genes required for autophagy, including Beclin1 systemically or Atg7 in only rod photoreceptors resulted in increased susceptibility to light-induced retinal damage. Increased photoreceptor cell death was observed when retinas lacking the rod photoreceptor-specific Atg7 gene were coincubated with 20 μm All-Trans-Retinal. Park2−/− mice also displayed light-induced retinal degeneration. Ultra-structural analyses showed mitochondrial and endoplasmic retireticulum impairment in retinas of these model animals after light exposure. Taken together, these observations provide novel evidence implicating an important role of autophagy and mitophagy in protecting the retina from All-Trans-Retinal– and light-induced degeneration.

Gabriel H Travis – One of the best experts on this subject based on the ideXlab platform.

  • non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
    bioRxiv, 2020
    Co-Authors: Rebecca Ward, Joanna J Kaylor, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, James B Hurley, Gabriel H Travis, Breandán N. Kennedy
    Abstract:

    Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protprotein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.

  • light driven regeneration of cone visual pigments through a mechanism involving rgr opsin in muller glial cells
    Neuron, 2019
    Co-Authors: Ala Morshedian, Joanna J Kaylor, Avian Tsan, Rikard Frederiksen, Lily Yuan, Alapakkam P Sampath, Roxana A Radu, Gordon L Fain, Gabriel H Travis
    Abstract:

    While rods in the mammalian retina regenerate rhodopsin through a well-characterized pathway in cells of the retinal pigment epithelium (RPE), cone visual pigments are thought to regenerate in part through an additional pathway in Muller cells of the neural retina. The proteins comprising this intrinsic retinal visual cycle are unknown. Here, we show that RGR opsin and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light. Isolated retinas from Rgr+/+ and Rgr-/- mice were exposed to continuous light, and cone photoresponses were recorded. Cones in Rgr-/- retinas lost sensitivity at a faster rate than cones in Rgr+/+ retinas. A similar effect was seen in Rgr+/+ retinas following treatment with the glial cell toxin, α-aminoadipic acid. These results show that RGR opsin is a critical component of the Muller cell visual cycle and that regeneration of cone visual pigment can be driven by light.

  • RESEARCH ARTICLE Diacylglycerol O-Acyltransferase Type-1 Synthesizes Retinyl Esters in the Retina and Retinal Pigment Epithelium
    , 2016
    Co-Authors: Joanna J Kaylor, Roxana A Radu, Nicholas Bischoff, Jacob Makshanoff, Marcia Lloyd, Shannan Eddington, Tran Bianconi, Dean Bok, Gabriel H Travis
    Abstract:

    Retinyl esters represent an insoluble storage form of vitamin A and are substrates for the retinoid isomerase (Rpe65) in cells of the retinal pigment epithelium (RPE). The major retinyl-ester synthase in RPE cells is lecithin:retinol acyl-transferase (LRAT). A second pal-mitoyl coenzyme A-dependent retinyl-ester synthase activity has been observed in RPE homogenates but the protein responsible has not been identified. Here we show that diacyl-glycerol O-acyltransferase-1 (DGAT1) is expressed in multiple cells of the retina including RPE and Müller glial cells. DGAT1 catalyzes the synthesis of retinyl esters from multiple ret-inol isomers with similar catalytic efficiencies. Loss of DGAT1 in dgat1-/-mice has no effect on retinal anatomy or the ultrastructure of photoreceptor outer-segments (OS) and RPE cells. Levels of visual chromophore in dgat1-/-mice were also normal. However, the normal build-up of all-trans-retinyl esters (all-trans-RE’s) in the RPE during the first hour after a deep photobleach of visual pigments in the retina was not seen in dgat1-/-mice. Further, total retinyl-ester synthase activity was reduced in both dgat1-/- retina and RPE