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      Effects of Diet and Strain on Mouse Serum and Tissue Retinoid Concentrations

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          Abstract

          The relationship between dietary vitamin A and all- trans-retinoic acid levels in serum and tissues had not been quantified. We determined the impact of dietary vitamin A on retinoid levels in serum, liver, kidney, testis, and epididymal white adipose of five mouse strains: AKR/J; BALB/cByJ; C3H/HeJ; C57BL/6J; 129S1/SvImJ. Retinoids were quantified in mice fed copious vitamin A (lab chow, ≥20 IU/g) followed by one month feeding a vitamin A-sufficient diet (4 IU/g), or after three generations of feeding a vitamin A-sufficient diet. Retinol and retinyl esters were measured by high-performance liquid chromatography with ultraviolet absorbance detection. All- trans-retinoic acid was quantified by liquid chromatography tandem mass spectrometry. The amounts of dietary vitamin A had long-term strain-specific effects on tissue retinyl ester, retinol and all- trans-retinoic acid concentrations. Three generations of feeding a vitamin A-sufficient diet decreased all- trans-retinoic acid in most tissues of most strains, in some cases more than 60%, compared to a diet with copious vitamin A. With both diets, all- trans-retinoic acid concentrations maintained an order of liver ≈ testis > kidney > white adipose tissue ≈ serum. Neither retinol nor all- trans-retinoic acid in serum reflected all- trans-retinoic acid concentrations in tissues. Strain and tissue-specific differences in retinol and all- trans-retinoic acid altered by different amounts of dietary vitamin A could have profound effects on retinoid action. This would be the case especially with the increased all- trans-retinoic acid values associated with the amounts of vitamin A and its precursors (carotenoids) in chow diets.

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          Most cited references13

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          Physiological insights into all-trans-retinoic acid biosynthesis.

          All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data support a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires the presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.
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            Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein.

            Retinol-binding protein (RBP) is the sole specific transport protein for retinol (vitamin A) in the circulation, and its single known function is to deliver retinol to tissues. Within tissues, retinol is activated to retinoic acid, which binds to nuclear receptors to regulate transcription of >300 diverse target genes. In the eye, retinol is also activated to 11-cis-retinal, the visual chromophore. We generated RBP knockout mice (RBP(-/-)) by gene targeting. These mice have several phenotypes. Although viable and fertile, they have reduced blood retinol levels and markedly impaired retinal function during the first months of life. The impairment is not due to developmental retinal defect. Given a vitamin A-sufficient diet, the RBP(-/-) mice acquire normal vision by 5 months of age even though blood retinol levels remain low. Deprived of dietary vitamin A, vision remains abnormal and blood retinol declines to undetectable levels. Another striking phenotype of the mutant mice is their abnormal retinol metabolism. The RBP(-/-) mice can acquire hepatic retinol stores, but these cannot be mobilized. Thus, their vitamin A status is extremely tenuous and dependent on a regular vitamin A intake. Unlike wild-type mice, serum retinol levels in adult RBP(-/-) animals become undetectable after only a week on a vitamin A-deficient diet and their retinal function rapidly deteriorates. Thus RBP is needed for normal vision in young animals and for retinol mobilization in times of insufficient dietary intake, but is otherwise dispensable for the delivery of retinol to tissues.
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              International Union of Pharmacology. LX. Retinoic acid receptors.

              Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARalpha, RARbeta, and RARgamma), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-trans-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                9 June 2014
                : 9
                : 6
                : e99435
                Affiliations
                [1]Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, United States of America
                Clermont Université, France
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JLN KMO MAK. Performed the experiments: KMO MAK. Analyzed the data: JLN KMO MAK. Contributed reagents/materials/analysis tools: JLN KMO MAK. Contributed to the writing of the manuscript: JLN KMO MAK.

                [¤]

                Current address: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, United States of America

                Article
                PONE-D-14-12470
                10.1371/journal.pone.0099435
                4049816
                24911926
                f99bbee5-690b-47bc-b747-576972ccafb9
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 March 2014
                : 13 May 2014
                Page count
                Pages: 5
                Funding
                This work was supported by the National Institutes of Health USA grants DK090522 and AA017927. JLN received this funding ( http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Developmental Biology
                Nutrition
                Engineering and Technology
                Industrial Engineering
                Industrial Processes
                Separation Processes
                Medicine and Health Sciences
                Endocrinology
                Metabolic Disorders
                Research and Analysis Methods
                Animal Studies
                Animal Models of Disease
                Extraction Techniques
                Model Organisms
                Research Design
                Specimen Preparation and Treatment
                Spectrum Analysis Techniques
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All data are included within the paper.

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