Hepatic retinoid metabolism and signaling in starvation and diabetes.

饥饿和糖尿病中的肝脏类维生素A代谢和信号传导。

• 批准号: 10394793
• 负责人: Natalia Y Kedishvili
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394793
• 关键词: Address; Adult; Affect; Anabolism; Bioinformatics; Biometry; Body Patterning; Carnitine Palmitoyltransferase I; Cell physiology; Circadian Rhythms; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; Embryo; Embryonic Development; Energy Metabolism; Ensure; Enzymes; Event; Fasting; Fatty-acid synthase; Foundations; Genes; Glucokinase; Goals; Health; Hepatic; Hour; Insulin-Dependent Diabetes Mellitus; Knowledge; Link; Liver; Mass Spectrum Analysis; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Molecular; Nuclear; Organism; Outcome; Outcome Study; Personal Satisfaction; Phosphoenolpyruvate Carboxylase; Physiology; Proteins; Proteomics; Retinoic Acid Receptor; Retinoids; Retinol dehydrogenase; Role; Signal Transduction; Starvation; Testing; Tissues; Tretinoin; Up-Regulation; Vitamin A; base; carbohydrate metabolism; cell type; fatty acid oxidation; in vitro Assay; insight; insulin signaling; ketogentic; lipid metabolism; metabolomics; mouse model; novel; response; stem; targeted treatment; therapeutically effective; transcription factor; transcriptome sequencing; translational impact

Liver is the central metabolic hub that coordinates the carbohydrate and lipid metabolism. The bioactive derivative of vitamin A, retinoic acid (RA) was shown to regulate a number of major metabolic genes including phosphoenolpyruvate carboxykinase, fatty acid synthase, carnitine palmitoyltransferase 1, and glucokinase among others. Expression levels of these genes undergo profound changes during metabolic transitions such as adaptation to starvation, or in response to insufficient insulin signaling during type 1 diabetes. However, it is not known whether the levels of RA in liver change during such metabolic remodeling, and how the changes in RA levels, in turn, might affect the liver’s capacity for metabolic adaptation. To start addressing this fundamental gap in our knowledge, we have carried out preliminary studies targeting hepatic retinoid metabolism and signaling in the well-fed state, in starvation, and in type 1 diabetes. These initial studies have yielded several novel and paradigm-shifting observations. First of all, our preliminary data indicate that fed-to- starved transition is associated with significant downregulation of hepatic RA biosynthesis and signaling that stems from the downregulation of hepatic retinol dehydrogenase activity, which is the rate-limiting step in RA biosynthesis. Second, our preliminary studies suggest that the decrease in the overall hepatic retinol dehydrogenase activity is associated with changes in subcellular localization of retinol dehydrogenase 10 and a decrease in its overall cellular abundance. Third, our preliminary studies suggest that, in contrast to starvation, the untreated type 1 diabetes is associated with upregulation of RA biosynthesis and signaling. This upregulation of RA biosynthesis appears to come about as a result of an increase in hepatic retinol dehydrogenase activity, which, in turn, correlates with the increase in cellular abundance of RDH10 and changes in its subcellular localization. Taken together, our preliminary studies suggest that the downregulation of hepatic RA biosynthesis and signaling is critical for an orderly adaptation to starvation. In contrast, the upregulation of hepatic RA biosynthesis and signaling in type 1 diabetes might be a harmful outcome contributing to the metabolic inflexibility associated with this disease. Importantly, our initial findings suggest the existence of a novel, previously unrecognized mechanism by which the hepatic RA biosynthesis is regulated through adjustments in subcellular localization and cellular abundance of retinol dehydrogenase 10. In this application, we propose to examine these novel concepts through the following Specific Aims: 1) to characterize the hepatic retinoid metabolism and signaling in the well-fed state and in starvation; and 2) to investigate the hepatic retinoid metabolism and signaling in type 1 diabetes. The results of these studies will uncover the molecular mechanisms responsible for coordination of RA levels with metabolic status of liver and will lay the foundation for development of better informed therapies targeting metabolic disease.

肝脏是协调碳水化合物和脂质代谢的中心代谢枢纽。维生素A的生物活性衍生物视黄酸（RA）显示出调节许多主要代谢基因，包括磷酸烯醇丙酮酸羧激酶、脂肪酸合酶、肉毒碱棕榈酰转移酶1和葡萄糖激酶等。这些基因的表达水平在代谢转换过程中发生深刻的变化，例如适应饥饿，或响应1型糖尿病期间胰岛素信号不足。然而，目前尚不清楚在这种代谢重塑过程中肝脏中的RA水平是否发生变化，以及RA水平的变化如何反过来影响肝脏的代谢适应能力。为了开始解决我们知识中的这一根本差距，我们已经进行了初步研究，目标是在良好的进食状态下，饥饿和1型糖尿病中的肝脏类维生素A代谢和信号传导。这些初步研究产生了一些新颖和范式转变的观察结果。首先，我们的初步数据表明，从进食到饥饿的转变与肝脏RA生物合成和信号传导的显著下调有关，该信号传导源于肝脏视黄醇脱氢酶活性的下调，这是RA生物合成中的限速步骤。第二，我们的初步研究表明，在整个肝脏视黄醇脱氢酶活性的降低与视黄醇脱氢酶10的亚细胞定位的变化和减少其整体细胞丰度。第三，我们的初步研究表明，与饥饿相反，未经治疗的1型糖尿病与RA生物合成和信号转导的上调有关。RA生物合成的这种上调似乎是由于肝视黄醇脱氢酶活性增加而引起的，而肝视黄醇脱氢酶活性增加又与RDH 10细胞丰度的增加及其亚细胞定位的变化相关。综上所述，我们的初步研究表明，下调肝脏RA的生物合成和信号传导是有序适应饥饿的关键。相反，1型糖尿病中肝脏RA生物合成和信号传导的上调可能是一种有害的结果，有助于与这种疾病相关的代谢不稳定性。重要的是，我们的初步研究结果表明，存在一种新的，以前未被认识的机制，通过该机制调节肝脏RA的生物合成，通过调节亚细胞定位和细胞丰度的视黄醇脱氢酶10。在本申请中，我们提出通过以下特定目的来检查这些新概念：1）表征良好进食状态和饥饿状态下的肝脏类维生素A代谢和信号传导;以及2）研究1型糖尿病中的肝脏类维生素A代谢和信号传导。这些研究的结果将揭示负责协调RA水平与肝脏代谢状态的分子机制，并将为开发针对代谢疾病的更好的知情疗法奠定基础。