Retinoid Homeostasis

类维生素A稳态

• 批准号: 9271964
• 负责人: JOSEPH L NAPOLI
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271964
• 关键词: Address; Adipocytes; Adult; Alcoholic Liver Diseases; All-Trans-Retinol; Anabolism; Autacoids; Autocrine Communication; Autophagocytosis; Binding Proteins; Biological; Cardiac development; Cell Differentiation process; Cell physiology; Cells; Data; Development; Diabetes Mellitus; Disease; Embryonic Development; Enzyme Kinetics; Enzymes; Esters; Fluorescence Microscopy; Gene Family; Goals; Hepatocyte; Homeostasis; Inflammation; Isoenzymes; Knock-out; Lecithin; Lipids; Location; Malignant Neoplasms; Mediating; Membrane; Metabolism; Methods; Mitochondria; Molecular; Mus; Muscle; Myopathy; Names; Nature; Nervous System Physiology; Obesity; Organelles; Outcome; Oxidoreductase; Paracrine Communication; Pattern; Phenotype; Process; Proteins; Proteomics; RalDH1; Reaction; Regulation; Research; Retinal; Retinal dehydrogenase; Retinoids; Retinol Binding Proteins; Retinol dehydrogenase; Role; Signaling Molecule; Site; Skeletal Development; Smooth Endoplasmic Reticulum; Source; Surface; Testing; Time; Transferase; Tretinoin; Vitamin A; Vitamin A Deficiency; atherogenesis; base; cell fate specification; cell type; cellular imaging; energy balance; enzyme activity; functional disability; immune function; insight; interest; knock-down; lecithin-retinol acyltransferase; lipid biosynthesis; lipid metabolism; metabolomics; migration; nervous system development; public health relevance; short chain trans-2-enoyl-CoA reductase; virtual

 DESCRIPTION (provided by applicant): 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.

 描述（由适用提供）：视黄醇（维生素A）的全反击酸（RA）的生物合成会产生一种自动化，可调节细胞脂肪规格和分化细胞的功能，包括燃料的使用，免疫功能和神经系统功能，仅举几例。短链脱氢酶/还原酶基因（SDR）家族的多种视黄醇脱氢酶（RDH）和还原酶（RRD）催化视黄醇转化为视网膜或视网膜变为视网膜。在小鼠中已经淘汰了三个：脱氢酶RDH1和RDH10；减少DHRS3。这三个淘汰赛分别揭示了与肥胖，神经系统发育和功能以及心脏和骨骼发育有关的维生素A缺陷表型。每个人在整个胚胎发生和成年人中都有宽度的表达。此外，剩余的减少DHRS3和视黄醇脱氢酶RDH10似乎形成了友好的异二聚体。视网膜脱氢酶（RALDH）催化了RA生物合成的第二步，视网膜不可逆地转化为RA。 raldh1，raldh2和raldh3的敲除表现出反映RA缺乏症的表型，但每个表型都不同，分别涉及能量平衡，免疫功能/胚胎生成和发育。这些数据表明，特定的代谢物（酶）组合，RDH/RRD/RALDH）会产生离散的RA池以支持不同的类固醇功能。尚未检查这些假定代谢物的协调调节和功能。这项研究的长期目标是确定RA生物合成的位点，每个变异物的生物学影响以及控制化学表达的机制。实际上，除白脂肪细胞外，所有细胞构成了多眼脂质液滴（LD）。 LD功能是可能产生自身运动的细胞器。但是，相对较少的研究集中在这种潜在的LD功能上。在LD生物合成之前，主要的视黄醇酯化酶，卵磷脂：视黄醇酰基转移（LRAT），以及RDH1的光滑内质网中。 CRBP1的主要细胞内视黄醇结合蛋白与线粒体或线粒体相关膜（MAM）定位，RDH10也是如此。在LD形成期间，LRAT，RDH10和DHRS3（而不是RDH1）位于LD的表面或附近。 LRAT和RDH10与LD的关联增加了其特异性酶活性。该项目将检验以下假设：LD结合了将视黄醇激活为RA的化学物质，该假设由视网膜类动物稳态的精选酶和结合蛋白组成。具体目的是：1）确定从肝细胞中分离出的LD中有助于类维生素性代谢的酶； 2）确定与LD相关的类维生素性生物代谢酶的亚细胞来源以及其与LD相互作用的确切性质； 3）确定类维生素性生物合成能力 ld。该项目将生成对类维生素性稳态，RA生物合成以及LD作为自身类体系来源的功能的重要数据，并将洞悉视视视网膜代谢在LD相关疾病（例如癌症，感染和糖尿病）方面的作用。