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.

肝脏是辅助碳水化合物和脂质代谢的中央代谢枢纽。维生素A，视黄酸（RA）的生物活性衍生物可调节许多主要的代谢基因，包括磷酸烯醇丙酮酸羧基酶，脂肪酸合酶，carnitine Palmitoyltransylansfrassferase 1和葡萄糖酶。这些基因的表达水平在代谢转变（例如适应饥饿或响应1型糖尿病期间的胰岛素信号不足）的过程中经历了深刻的变化。但是，尚不清楚这种代谢重塑期间肝脏变化的RA水平是否是否会影响RA水平的变化反过来可能影响肝脏的代谢适应能力。为了开始解决这一基本差距，我们已经进行了针对肝类视黄素代谢和信号传导的初步研究，饥饿和1型糖尿病。最初的研究产生了几本小说和范式转移观察结果。首先，我们的初步数据表明，饲喂到饥饿的过渡与肝RA生物合成的显着下调和信号传导有关，这是肝视黄醇脱氢酶活性下调的步骤，这是RA生物合成的速率限制阶段。其次，我们的初步研究表明，总体肝视黄醇脱氢酶活性的降低与视黄醇脱氢酶10的亚细胞定位变化有关，其整体细胞丰度降低。第三，我们的初步研究表明，与饥饿相比，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。 RA生物合成的这种上调似乎是由于肝乙醇脱氢酶活性的增加而出现的，这反过来又与RDH10的细胞抽象增加以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，肝RA生物合成和信号传导的下调对于有序适应饥饿至关重要。相反，1型糖尿病中肝RA生物合成和信号传导的上调可能是有害结果，导致与该疾病相关的代谢不灵活性。 Importantly, our Initial findings suggest the existence of a novel, previously unrecognized mechanism by which the hepatitic RA biosynthesis is regulated through adjustments in subcellular localization and cellular abstraction of retinol dehydrogenase 10. In this application, we propose to examine these novel concepts through the following Specific Aims: 1) to characterize the hepatitic retinoid metabolism and signaling in the well-fed state and in starvation; 2）研究1型糖尿病中类维生素性代谢和信号传导。这些研究的结果将揭示负责RA水平与肝脏代谢状态的协调水平的分子机制，并将为靶向代谢疾病的更好知情疗法的发展奠定基础。