Postprandial Vitamin A

描述（由申请人提供）：维生素A是人体维持许多重要生理功能所必需的，包括正常生长和发育、健康的免疫反应、正常生殖和正常视力。由于维生素A在许多基本生理过程中的重要性，身体已经发展出储存维生素A的能力，主要在肝脏中，但也在脂肪组织中。目前，关于肝细胞和肝星状细胞（HSC）中负责维生素A储存和代谢的分子过程的细节相对较少，这两种肝细胞类型参与维生素A的储存和代谢。类似地，对于脂肪细胞中介导维生素A储存和代谢的重要分子过程知之甚少，脂肪组织中的细胞类型负责维生素A的积累。本申请中提出的研究旨在提供对这些过程的新的和更详细的理解。 该项目的总体目标是确定RBP如何从HSC和脂肪细胞储存中动员视黄醇。这项研究将在以细胞类型特异性方式表达视黄醇结合蛋白（RBP）的小鼠中进行。具体目标1探讨了RBP在肝细胞中特异性合成的作用，特别是在HSC或两种细胞类型中，在动员HSC维生素A储存进入循环中。20多年来，这一直是一个相当有争议的问题。具体目标1的一个根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（房室）模型，描述肝细胞、HSC、循环和外周组织中视黄醇的通量，以及肝细胞和/或HSC中RBP的表达对其的影响。脂肪细胞也是体内维生素A储存的重要场所，也是RBP合成的重要场所。重要的是，已经提出由脂肪细胞合成的RBP起到降低全身胰岛素反应性的作用。RBP在促进维生素A从脂肪细胞动员中的作用或这与胰岛素信号传导的关系知之甚少。具体目标2将定义RBP在促进维生素A从脂肪细胞动员中的作用，确定脂肪细胞分泌RBP是否依赖于视黄醇的可用性，并描述这如何与脂肪来源的RBP在信号传导外周组织中的作用联系起来，使胰岛素反应性降低，从而引起II型糖尿病。

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.