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。

基本信息

批准号：
10541248
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
项目类别：
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/10541248
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 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

项目摘要

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) 可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、肉碱棕榈酰转移酶 1 和葡萄糖激酶。这些基因的表达水平在代谢转变过程中发生深刻的变化，例如适应饥饿，或在 1 型糖尿病期间响应胰岛素信号不足。目前尚不清楚肝脏中的 RA 水平是否会在这种代谢重塑过程中发生变化，以及 RA 水平的变化如何影响肝脏的代谢适应能力。我们针对进食充足状态、饥饿状态和 1 型糖尿病中的肝脏类视黄醇代谢和信号传导进行了初步研究，这些初步研究得出了一些新颖且颠覆性的观察结果。 -饥饿过渡与肝脏 RA 生物合成和信号传导的显着下调相关，这是由于肝脏视黄醇脱氢酶活性的下调，这是 RA 生物合成的限速步骤。其次，我们的初步研究表明，总体肝脏视黄醇脱氢酶活性的降低与与视黄醇脱氢酶 10 的亚细胞定位的变化及其整体细胞丰度的减少有关。第三，我们的初步研究表明，相反。饥饿时，未经治疗的 1 型糖尿病与 RA 生物合成和信号传导的上调有关，这种 RA 生物合成的上调似乎是由于肝脏视黄醇脱氢酶活性增加而导致的，而这又与细胞内视黄醇脱氢酶活性的增加有关。综上所述，我们的初步研究表明，肝脏 RA 生物合成和信号传导的下调对于 RDH10 的丰度及其亚细胞定位的变化至关重要。相比之下，1 型糖尿病中肝脏 RA 生物合成和信号传导的上调可能会导致与该疾病相关的代谢不灵活，这一结果很重要，我们的初步研究结果表明存在一种以前未被认识的新机制。通过调整视黄醇脱氢酶 10 的亚细胞定位和细胞丰度来调节肝脏 RA 生物合成。在本申请中，我们建议通过以下方式研究这些新概念：具体目标如下：1) 表征进食充足状态和饥饿状态下的肝脏类维生素A代谢和信号传导；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分子水平。负责协调 RA 水平与肝脏代谢状态的机制，将为开发针对代谢疾病的更明智的疗法奠定基础。