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Grant Abstract: Retinoid Homeostasis

Grant Number: 5R01DK102014-04
PI Name: Napoli
Project Title: Retinoid Homeostasis

Abstract: Biosynthesis of all-trans-retinoic acid (RA) from retinol (vitamin A) produces an autacoid that regulates cell fate specification and functions of differentiated cells, including fuel use, immune function, and nervous system function, to name a few. Multiple retinol dehydrogenases (Rdh) and reductases (RRD) of the short-chain dehydrogenase/reductase gene (SDR) family catalyze conversion of retinol into retinal or retinal into retinol. Three have been knocked out in mice: the dehydrogenases Rdh1 and Rdh10; the reductase Dhrs3. These three knockouts each reveal a vitamin A-deficiency phenotype, associated with adiposity, nervous system development and function, and cardiac and skeletal development, respectively. Each has widespread expression throughout embryogenesis and in the adult. In addition, the retinal reductase Dhrs3 and the retinol dehydrogenase Rdh10 seem to form a facilitative heterodimer. Retinal dehydrogenases (Raldh) catalyze the second step of RA biosynthesis, irreversible conversion of retinal into RA. Knockouts of Raldh1, Raldh2, and Raldh3, show phenotypes reflecting RA deficiency, but each is distinct, involving energy balance, immune function/embryogenesis, and development, respectively. These data suggest that specific metabolons (enzyme combinations, Rdh/RRD/Raldh) generate discrete RA pools to support distinct retinoid functions. Coordinated regulation and function of these putative metabolons have not been examined. The long-term goals of this research are to determine sites of RA biosynthesis, biological impact of each metabolon, and mechanisms of regulating metabolon expression. Virtually all cells, except white adipocytes, form multilocular lipid droplet (LD). LD function as organelles that may generate autacoids. Relatively little research has focused on this potential LD function, however. Before LD biosynthesis, the major retinol esterifying enzyme, lecithin:retinol acyl transferase (LRAT), localizes in the smooth endoplasmic reticulum, as does Rdh1. The major intracellular retinol binding-protein, Crbp1 localizes with mitochondria or mitochondria associated membranes (MAM), as does Rdh10. During LD formation Crpb1, LRAT, Rdh10 and Dhrs3, but not Rdh1, locate at or near surfaces of LD. Association of LRAT and Rdh10 with LD increases their specific enzyme activity. This project will test the hypothesis that LD incorporate a metabolon for activating retinol into RA, which consists of select enzymes and binding-proteins of retinoid homeostasis. The specific aims are: 1) identify enzymes that contribute to retinoid metabolism in LD isolated from hepatocytes; 2) determine subcellular origin(s) of retinoid-metabolizing enzymes that associate with LD and the precise nature of their interactions with LD; 3) determine the retinoid biosynthesizing capacity of LD. This project will generate data significant to retinoid homeostasis, RA biosynthesis, and the function of LD as sources of autacoids, and will provide insight into the role of retinoid metabolism with respect to LD- associated diseases, such as cancer, inflammation, and diabetes. PUBLIC HEALTH RELEVANCE: LD are organelles that may generate lipid signaling molecules known as autacoids. Errors of LD-mediated metabolism cause or contribute to diseases, such as inflammation, cancer, diabetes, and aberrations in muscle fat metabolism, all processes controlled by retinoids. This project will generate insight into the contributions of LD to disease and the nature of LD-associated diseases, by determining their ability to generate the autacoid retinoic acid, which controls multiple cellular processes.

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