Function of 9-cis-retinoic acid

9-顺式视黄酸的功能

• 批准号: 8323873
• 负责人: JOSEPH L NAPOLI
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-24 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323873
• 关键词: 9-cis-retinal; Adipose tissue; All-Trans-Retinol; Anabolism; Attenuated; Autacoids; Biological Assay; Blood Glucose; Brain; Calcium; Cell Line; Cells; Citrates; Data; Defect; Disease; Dose; Energy Metabolism; Evaluation; Fasting; Gene Family; Genes; Genomics; Glucokinase; Gluconeogenesis; Glucose; Glucose tolerance test; Goals; Hormones; Hypoglycemia; Insulin; Isocitrates; Left; Liver; Mediating; Messenger RNA; Metabolic Diseases; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Oxidoreductase; Pancreas; Pharmaceutical Preparations; Physiological; Post-Translational Protein Processing; Principal Investigator; Process; Regulation; Research; Retinoids; Serum; Testing; Work; alitretinoin; analog; blood glucose regulation; feeding; glycogenolysis; impaired glucose tolerance; in vivo; insight; insulin secretion; islet; isocitrate; liquid chromatography mass spectrometry; member; non-genomic; novel; pancreas development; prevent; programs; receptor function

DESCRIPTION (provided by applicant): Program Director/Principal Investigator (Last, First, Middle): Napoli, Joseph. L. This research has long-term goals to determine 9-cis-retinoic acid (9cRA) physiological function and mechanisms of action. 9cRA has diverse pharmacological actions, which have prompted evaluation of analogs (rexinoids) for treating metabolic disease. Yet, 9cRA has not been detected in vivo in liver, serum, brain, adipose et al. with a sensitive LC/MS/MS assay, leaving its status unsettled (autacoid or drug?). The data here identify 9cRA in vivo (only in pancreas), show that 2-cells biosynthesize 9cRA, and that glucose induces mRNA of the cis-retinoid reductase Dhrs3 (4-fold) and represses mRNA of the cis-retinoid dehydrogenase Rdh5 (10-fold) in 832/13 cells. We also show that 9cRA decreases insulin secretion from isolated mouse islets by 70% within 15 min, and in the 2-cell line 832/13 by reducing Glut2 and glucokinase activities, ATP and calcium. Dosing 9cRA impairs glucose tolerance in vivo and reduces serum insulin during a glucose tolerance test. 9cRA decreases in the transition from the fasted to the fed state, and glucose dosing reduces 9cRA in vivo >80% within 15 min. These data support a model in which 9cRA and glucose work in opposition to regulate glucose-stimulated insulin secretion, and indicate non-genomic mechanisms of action for 9cRA (in addition to genomic mechanisms of action). In the longer term, 9cRA decreases expression of at least two genes crucial for pancreas development and insulin secretion: Pdx-1 and HNF41. Notably, this shows that at least two of the six monogenic diseases known as maturity onset diabetes of the young (MODY) are caused by defects in genes regulated by 9cRA, i.e. defects in Pdx-1 and HNF41 underlie MODY4 and MODY1, respectively. A defect in the gene that encodes glucokinase underlies a third MODY, i.e. MODY 2: 9cRA modulates glucokinase activity. These data validate 9cRA as a naturally occurring retinoid with physiological function(s) unique among retinoids, and identify a novel component of 2-cells that contributes to insulin secretion. This project will test 9cRA function as an autacoid that attenuates insulin secretion during low glucose to prevent hypoglycemia. The specific aims are to determine: 1) physiological function(s) of 9cRA in short-term regulation of glucose stimulated insulin secretion; 2) mechanisms of rapid 9cRA actions that diminish insulin secretion; 3) whether 9cRA requires RAR for non-genomic and/or genomic actions in the 2- cell; 4) functions of Dhrs3 and Rdh5 in 2-cell 9cRA biosynthesis. Aim 1 will test the hypothesis that modest increases in 9cRA desensitize the pancreas to glucose, and that increasing blood glucose overcomes ability of 9cRA to impair insulin secretion. Aim 2 will test the hypothesis that 9cRA functions through post-translational modification of Glut2 and GK. Aim 3 will test the hypothesis that non-genomic and genomic actions of RAR mediate the actions of 9cRA in the 2-cell. Aim 4 will test the hypothesis that glucose controls 9cRA in the 2-cell through Dhrs3 and Rdh5. This project should contribute novel insight into mechanisms of retinoid action, nuclear hormone receptor function, regulation of Glut2 and GK, and insulin secretion. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述(由申请人提供)： 项目主任/首席调查员(最后、第一、中间)：约瑟夫·那不勒斯。本研究的长期目标是确定9-顺式维甲酸(9cRA)的生理功能和作用机制。9cRA具有不同的药理作用，这促使人们评估类似物(Rexinoid)用于治疗代谢性疾病。然而，在肝脏、血清、脑、脂肪等组织中尚未检测到9cRA。用灵敏的LC/MS/MS分析，使其状态悬而未决(金刚类药物或药物？)。在832/13细胞中，葡萄糖诱导顺式维甲酸还原酶Dhrs3的mRNA(4倍)，抑制顺式维甲酸脱氢酶Rdh5的mRNA(10倍)。我们还表明，9cRA在15分钟内使小鼠胰岛的胰岛素分泌减少了70%，在2-细胞系832/13中，9cRA通过降低Glut2和葡萄糖激酶活性、ATP和钙而减少了胰岛素的分泌。服用9cRA会损害体内的葡萄糖耐量，并在糖耐量试验中降低血清胰岛素。9cRA在从禁食状态到摄食状态的转变过程中降低，在体内葡萄糖剂量在15分钟内减少了80%。这些数据支持9cRA和葡萄糖相反地调节葡萄糖刺激的胰岛素分泌的模型，并表明9cRA的非基因组作用机制(除了基因组作用机制外)。从长远来看，9cRA减少了至少两个对胰腺发育和胰岛素分泌至关重要的基因的表达：PDX-1和HNF41。值得注意的是，这表明在被称为青年成熟型糖尿病(MODY)的六种单基因疾病中，至少有两种是由9cRA调控的基因缺陷引起的，即PDX-1和HNF41缺陷分别是MODY4和MODY1的基础。第三个MODY，即MODY 2：9cRA，编码葡萄糖激酶的基因存在缺陷。这些数据验证了9cRA是维甲酸中独一无二的具有生理功能的天然维甲酸(S)，并确定了一种有助于胰岛素分泌的新的2-细胞成分。这个项目将测试9cRA作为一种金盏花环的功能，在低糖期间减弱胰岛素的分泌，以防止低血糖。其具体目的是确定：1)9cRA在短期调节葡萄糖刺激的胰岛素分泌中的生理功能(S)；2)9cRA快速作用于减少胰岛素分泌的机制；3)9cRA在2-细胞中是否需要RAR进行非基因组和/或基因组作用；4)Dhrs3和Rdh5在2-细胞9cRA生物合成中的作用。目的1将验证这样的假设，即9cRA的适度增加使胰腺对葡萄糖不敏感，并且血糖的增加克服了9cRA损害胰岛素分泌的能力。目的2验证9cRA通过Glut2和GK的翻译后修饰发挥作用的假说。目的3验证RAR的非基因组和基因组作用介导9cRA在2-细胞中作用的假说。目的4将验证葡萄糖通过Dhrs3和Rdh5控制2-细胞中9cRA的假设。该项目将对维甲酸的作用机制、核激素受体功能、Glut2和GK的调节以及胰岛素分泌提供新的见解。PHS 398/2590(06/09版)页面续格式页面