Hepatic retinoid metabolism and signaling in starvation and diabetes.

肝脏是协调碳水化合物和脂肪代谢的中心代谢中枢。维生素A的生物活性衍生物维甲酸(RA)可调节多种主要代谢基因，包括磷酸烯醇式丙酮酸羧酸激酶、脂肪酸合成酶、肉碱棕榈酰基转移酶1和葡萄糖激酶等。这些基因的表达水平在代谢转变期间经历了深刻的变化，例如对饥饿的适应，或者在1型糖尿病期间对胰岛素信号不足的反应。然而，目前尚不清楚在这种代谢重塑过程中，肝脏中的RA水平是否会发生变化，以及RA水平的变化会如何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，我们进行了针对肝脏维甲酸代谢和信号的初步研究，这些研究在营养良好、饥饿和1型糖尿病的状态下进行。这些初步研究已经产生了几个新颖的、改变范式的观察结果。首先，我们的初步数据表明，从喂食到饥饿的转变与肝脏RA生物合成的显著下调以及由肝脏视黄醇脱氢酶活性下调而产生的信号有关，而视黄醇脱氢酶活性是RA生物合成的限速步骤。第二，我们的初步研究表明，肝脏总视黄醇脱氢酶活性的降低与视黄醇脱氢酶10亚细胞定位的改变和总细胞丰度的降低有关。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的增加，而这反过来又与RDH10细胞丰度的增加和其亚细胞定位的变化有关。综上所述，我们的初步研究表明，肝脏RA生物合成和信号的下调对于有序适应饥饿至关重要。相反，1型糖尿病患者肝脏RA生物合成和信号的上调可能是一种有害的结果，导致与该疾病相关的代谢不灵活。重要的是，我们的初步发现表明，存在一种先前未知的新机制，通过调节视黄醇脱氢酶10的亚细胞定位和细胞丰度来调节肝脏RA的生物合成。在这一应用中，我们建议通过以下特定目的来检验这些新概念：1)表征肝脏在营养充足和饥饿状态下的维甲酸代谢和信号；以及2)研究1型糖尿病患者的肝脏维甲酸代谢和信号转导。这些研究的结果将揭示RA水平与肝脏代谢状态协调的分子机制，并将为开发针对代谢性疾病的更好的知情治疗奠定基础。

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.