Postprandial Vitamin A

描述(申请人提供)：维生素A是维持身体许多重要的生理功能所必需的，包括正常的生长和发育，健康的免疫反应，正常的生殖和正常的视力。由于维生素A在许多重要的生理过程中的重要性，人体已经发展出一种储存维生素A的能力，主要是在肝脏中，也在脂肪组织中。目前，肝细胞和肝星状细胞(HSCs)中参与维生素A储存和代谢的两种肝细胞参与维生素A储存和代谢的分子过程知之甚少。同样，人们对脂肪细胞中重要的调节维生素A储存和代谢的分子过程知之甚少。脂肪细胞是脂肪组织中负责维生素A积累的细胞类型。本申请书中提议的调查旨在提供对这些过程的新的和更详细的了解。该项目的总体目标是确定RBP如何从HSC和脂肪细胞库中动员视黄醇。拟议中的研究将在以特定细胞类型表达视黄醇结合蛋白(RBP)的小鼠身上进行。具体目的1探讨RBP在肝细胞，特别是在HSCs或在两种细胞类型中，在动员HSC维生素A储存进入循环中所起的作用。20多年来，这一直是一个颇具争议的问题。具体目标1的一个基本目标是解决这一争议。作为特定目标1的一部分，我们将开发一个数学(隔室)模型，描述视黄醇在肝细胞、肝干细胞、循环和外周组织之间的流量，以及RBP在肝细胞和/或肝干细胞中的表达是如何影响这一流量的。脂肪细胞也是体内维生素A储存的重要部位，也是RBP合成的重要部位。重要的是，有研究表明，由脂肪细胞合成的RBP会降低全身的胰岛素反应性。RBP在促进脂肪细胞维生素A动员中的作用或这可能与胰岛素信号有关的作用知之甚少。具体目标2将确定RBP在促进脂肪细胞动员维生素A方面的作用，确定脂肪细胞分泌RBP是否依赖于视黄醇的可获得性，并描述这可能与脂肪来源的RBP在信号转导外周组织变得不那么胰岛素反应，从而导致II型糖尿病的作用有何联系。

DESCRIPTION (provided by applicant): Vitamin A is required by the body for maintaining many important physiological functions including normal growth and development, a healthy immune response, normal reproduction, and normal vision. Owing to the importance of vitamin A in so many essential physiological processes, the body has developed an ability to store vitamin A, primarily in liver but also in adipose tissue. At present, relatively few details are known about the molecular processes responsible for vitamin A storage and metabolism in hepatocytes and hepatic stellate cells (HSCs), the two liver cell types involved in vitamin A storage and metabolism. Similarly, relatively little is known about the molecular processes that are important for mediating vitamin A storage and metabolism in adipocytes, the cell type in adipose tissue responsible for vitamin A accumulation. The investigations proposed in this application are aimed at providing new and more detailed understanding of these processes. The overall goal of the project is to establish how RBP mobilizes retinol from HSC and adipocyte stores. The studies being proposed will be carried out in mice that express retinol-binding protein (RBP) in a cell type-specific manner. Specific Aim 1 explores the roles that RBP synthesized specifically in hepatocytes, specifically in HSCs or in both cell types have in the mobilization of HSC vitamin A stores into the circulation. This has been a matter of considerable controversy for over 20 years. An underlying goal of Specific Aim 1 is to resolve this controversy. As part of Specific Aim 1 we will develop a mathematical (compartmental) model describing the flux of retinol amongst hepatocytes, HSCs, the circulation, and peripherial tissues and how this is influenced by expression of RBP in hepatocytes and/or HSCs. Adipocytes are also a significant site of vitamin A storage in the body and also an important site of RBP synthesis. Importantly, it has been proposed that RBP synthesized by adipocytes acts to lessen whole body insulin responsiveness. Little is known the role of RBP in facilitating vitamin A mobilization from adipocytes or how this might relate to insulin signaling. Specific Aim 2 will define the role of RBP in facilitating vitamin A mobilization from adipocytes, establish whether adipocyte secretion of RBP is dependent on retinol availability, and delineate how this may be linked to role of adipose-derived RBP in signaling peripheral tissues to become less insulin responsive, giving rise to type II diabetes.