Function of 9-cis-retinoic acid

9-顺式视黄酸的功能

• 批准号: 8186401
• 负责人: JOSEPH L NAPOLI
• 金额: $ 36.99万
• 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/8186401
• 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 PUBLIC HEALTH RELEVANCE: Program Director/Principal Investigator (Last, First, Middle): Napoli, Joseph. L. This research would determine physiological function and mechanisms of 9-cis-retinoic acid (9cRA) action in the pancreas. Supporting data indicate that 9cRA functions in opposition to glucose to modulate insulin secretion. Insight into this heretofore overlooked aspect of regulating insulin secretion promises to provide new understanding of the process of regulating insulin secretion, a major hormone that modulates energy metabolism. 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）：Napoli，Joseph。 L. 这项研究的长期目标是确定 9-顺式视黄酸 (9cRA) 的生理功能和作用机制。 9cRA 具有多种药理作用，这促使人们对治疗代谢性疾病的类似物（rexinoids）进行评估。然而，在体内肝脏、血清、脑、脂肪等中尚未检测到9cRA。使用灵敏的 LC/MS/MS 检测，使其状态不稳定（自体药还是药物？）。这里的数据在体内鉴定了 9cRA（仅在胰腺中），显示 2 细胞生物合成 9cRA，并且葡萄糖在 832/13 细胞中诱导顺式视黄醇还原酶 Dhrs3 的 mRNA（4 倍）并抑制顺式视黄醇脱氢酶 Rdh5 的 mRNA（10 倍）。我们还表明，9cRA 在 15 分钟内使离体小鼠胰岛的胰岛素分泌减少 70%，在 2 细胞系 832/13 中，通过减少 Glut2 和葡萄糖激酶活性、ATP 和钙。服用 9cRA 会损害体内葡萄糖耐量，并在葡萄糖耐量测试期间降低血清胰岛素。 9cRA 在从禁食状态到进食状态的转变中降低，并且葡萄糖剂量在 15 分钟内使体内 9cRA 降低 >80%。这些数据支持一个模型，其中 9cRA 和葡萄糖相反地调节葡萄糖刺激的胰岛素分泌，并表明 9cRA 的非基因组作用机制（除了基因组作用机制之外）。从长远来看，9cRA 会降低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，这表明被称为成年期发病的青少年糖尿病 (MODY) 的六种单基因疾病中至少有两种是由 9cRA 调节的基因缺陷引起的，即分别是 MODY4 和 MODY1 背后的 Pdx-1 和 HNF41 缺陷。编码葡萄糖激酶的基因缺陷是第三个 MODY 的基础，即 MODY 2: 9cRA 调节葡萄糖激酶活性。这些数据验证了 9cRA 是一种天然存在的类视黄醇，具有类视黄醇中独特的生理功能，并鉴定了 2-细胞中有助于胰岛素分泌的新成分。该项目将测试 9cRA 作为一种自体激素的功能，在低血糖期间减弱胰岛素分泌以预防低血糖。具体目标是确定： 1) 9cRA 在短期调节葡萄糖刺激的胰岛素分泌中的生理功能； 2) 9cRA 减少胰岛素分泌的快速作用机制； 3) 9cRA是否需要RAR才能在2-细胞中发挥非基因组和/或基因组作用； 4) Dhrs3和Rdh5在2细胞9cRA生物合成中的功能。 目标 1 将检验以下假设：9cRA 的适度增加会使胰腺对葡萄糖不敏感，并且血糖升高会克服 9cRA 损害胰岛素分泌的能力。 目标 2 将检验 9cRA 通过 Glut2 和 GK 的翻译后修饰发挥作用的假设。 目标 3 将检验以下假设：RAR 的非基因组和基因组作用介导 2 细胞中 9cRA 的作用。 目标 4 将检验葡萄糖通过 Dhrs3 和 Rdh5 控制 2 细胞中 9cRA 的假设。 该项目将为类视黄醇作用机制、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（修订版 06/09） 页面延续 格式页面 公共卫生相关性： 项目总监/首席研究员（最后，第一，中间）：Napoli，Joseph。 L. 这项研究将确定 9-顺式视黄酸 (9cRA) 在胰腺中的生理功能和作用机制。支持数据表明 9cRA 的功能与葡萄糖相反，可调节胰岛素分泌。对胰岛素分泌调节这一迄今为止被忽视的方面的深入研究有望为调节胰岛素分泌的过程提供新的认识，胰岛素分泌是调节能量代谢的主要激素。 PHS 398/2590（修订版 06/09） 页面延续 格式页面