Function of 9-cis-retinoic acid

9-顺式视黄酸的功能

• 批准号: 8461942
• 负责人: JOSEPH L NAPOLI
• 金额: $ 30.81万
• 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/8461942
• 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）： 项目总监/首席研究员（最后，第一，中间）：那不勒斯，约瑟夫。 L.这项研究的长期目标是确定9- cis-反毒酸（9cra）生理功能和作用机制。 9CRA具有多种药理作用，这促使对治疗代谢疾病的类似物（rexinoids）评估。然而，尚未在肝，血清，脑，脂肪等人的体内检测到9cra。具有敏感的LC/MS/MS分析，其状态尚未确定（Autacoid或Drug？）。这里的数据在体内（仅在胰腺中）识别9克拉，表明2细胞生物合成9cra，葡萄糖诱导顺式素还原酶DHRS3的mRNA（4倍）（4倍），并抑制顺式脱氢酶RDH5（10-10-Foldold）的顺式脱发素脱氢酶RDH5（10-322/1）。我们还表明，9CRA在15分钟内将胰岛素的分泌减少了70％，在2细胞线832/13中，通过减少GLUT2和葡萄糖激酶活性，ATP和钙。剂量9CRA会损害体内葡萄糖耐受性，并在葡萄糖耐量测试中降低血清胰岛素。 9cra从禁食到美联储状态下降，葡萄糖剂量在15分钟内降低了9cra> 80％。这些数据支持了一个模型，其中9CRA和葡萄糖在反对调节葡萄糖刺激的胰岛素分泌方面起作用，并指示了9CRA的非基因组作用机制（除了作用基因组机制外）。从长远来看，9CRA降低了至少两个对于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，六种单基因疾病中的至少两种被称为年轻人（Mody）的成熟糖尿病（MODY）是由9CRA调控的基因缺陷引起的，即PDX-1和HNF41的缺陷分别是Mody4和Mody4和Mody1的基础。编码葡萄糖酶的基因缺陷是第三个神经的基础，即Mody 2：9cra调节葡萄糖酶活性。这些数据将9CRA验证为一种天然发生的类维生素，具有在类视黄素中独特的生理功能，并确定了有助于胰岛素分泌的2细胞的新成分。该项目将测试9CRA功能作为一种自闭症，可减少低葡萄糖期间胰岛素分泌以预防低血糖症。具体目的是确定：1​​）在短期调节葡萄糖刺激的胰岛素分泌中，9cra的生理功能； 2）快速9克拉作用的机制减少了胰岛素分泌； 3）9cra是否需要2个细胞中非基因组和/或基因组作用的RAR； 4）DHRS3和RDH5在2细胞9CRA生物合成中的功能。 AIM 1将检验以下假设：9克拉脱敏胰腺脱敏至葡萄糖的脱敏，并且增加的血糖克服了9cra损害胰岛素分泌的能力。 AIM 2将检验以下假设，即9CRA通过glut2和GK的翻译后修饰起作用。 AIM 3将检验以下假设：RAR的非基因组和基因组作用介导9CRA在2细胞中的作用。 AIM 4将测试葡萄糖通过DHRS3和RDH5在2细胞中控制9CRA的假设。 该项目应促进对视视性类似作用机制，核激素受体功能，GLUT2和GK的调节以及胰岛素分泌的新洞察力。 PHS 398/2590（修订版06/09）页面延续格式页面