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（由申请人提供）：从视黄醇（维生素 A）生物合成全反式视黄酸（RA）产生一种自体物质，可调节细胞命运规范和分化细胞的功能，包括燃料使用、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黄醛或视黄醛转化为视黄醇，其中三种基因已在小鼠体内被敲除：脱氢酶 Rdh1 和 Rdh10；还原酶 Dhrs3。这三种基因敲除均揭示了与肥胖、神经系统发育和功能相关的维生素 A 缺乏表型。 ，以及心脏和骨骼发育，分别在整个胚胎发生和成人中广泛表达。此外，视网膜还原酶 Dhrs3 和视黄醇脱氢酶 Rdh10 似乎形成促进性异二聚体 (Raldh) 催化 RA 生物合成的第二步，即 Raldh1、Raldh2 和 Raldh3 的敲除，显示出反映 RA 缺陷的表型，但每个表型都是不同的。这些数据分别涉及能量平衡、免疫功能/胚胎发生和发育。代谢物（酶组合，Rdh/RRD/Raldh）产生离散的 RA 池以支持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。每种代谢物的生物学影响以及调节代谢物表达的机制几乎所有细胞（白色脂肪细胞除外）都形成多房脂滴（LD）。然而，在 LD 生物合成之前，主要的视黄醇酯化酶卵磷脂：视黄醇酰基转移酶 (LRAT) 与 Rdh1 一样，定位于平滑内质网。主要的细胞内视黄醇结合蛋白 Crbp1 定位于线粒体或线粒体相关膜 (MAM)。 Rdh10。在 LD 形成过程中，Crpb1、LRAT、Rdh10 和 Dhrs3（但不是 Rdh1）位于 LD 表面或附近。LRAT 和 Rdh10 与 LD 的结合会增加其特定酶活性。将视黄醇激活为 RA，其由特定的酶和类视黄醇稳态的结合蛋白组成。有助于从肝细胞分离的 LD 中的类视黄醇代谢；2) 确定与 LD 相关的类视黄醇代谢酶的亚细胞起源以及它们与 LD 相互作用的精确性质；3) 确定 LD 的类视黄醇生物合成能力； 该项目将生成对类视黄醇稳态、RA 生物合成和 LD 作为自体激素来源的功能具有重要意义的数据，并将深入了解类视黄醇代谢在 LD 相关疾病（如癌症、炎症和癌症）中的作用。糖尿病。