Vitamin A Storage and Metabolism

描述（由申请方提供）：肝脏是体内维生素A储存的主要组织部位，肝星状细胞（HSC）（也称为Ito细胞、脂肪储存细胞或脂肪细胞）是肝脏内维生素A储存的主要细胞部位。肝脏维生素A储备作为缓冲，以防止饮食维生素A摄入不足和过量的不良后果。几乎所有的肝脏维生素A都存在于HSC中存在的大细胞质脂滴（LD）中。这些LD的数量，大小和维生素A（视黄酯）含量随着膳食维生素A摄入量的增加而增加，并随着膳食摄入量不足而减少。HSC LD是一种特殊的亚细胞器，其唯一已知的生理功能是促进维生素A储存。这与其他肝脏LD不同，例如肝细胞中的LD，其在中性脂质（甘油三酯和胆固醇）储存和代谢中具有更广泛的作用。HSC LD相对较大的视黄酯含量及其对膳食维生素A摄入的反应性使其与存在于身体其他细胞类型中的其他LD非常不同。然而，对HSC LD的发生或维持或对此至关重要的生化和分子事件知之甚少。我们的研究将建立对HSC LD形成和维持至关重要的生化和分子过程，以及这些过程如何与维生素A储存和从肝脏动员有关。这个项目将解决3个基本问题，关于肝硬化LD生化和维生素A的储存和代谢在肝脏。目的1提出表征和研究小鼠HSC LDs在过量、正常（对照）或维生素A摄入不足时的蛋白质组。目标2中提出的研究源于我们已发表的研究，表明缺乏卵磷脂：视黄醇酰基转移酶（LRAT）的小鼠（负责HSC中视黄酯形成的酶）也缺乏HSC中的LD，但不是肝细胞。这是非常令人惊讶的，因为对于维持对照饮食的啮齿动物，视黄酯占液滴中存在的总脂质的小于40%。在目标2中，我们提出研究为什么LRAT是需要HSC LD形成。最后，在目标3中，我们将研究维生素A是如何从HSC动员的，以及这是否需要肝细胞中合成的血清视黄醇结合蛋白（RBP）的直接参与。

DESCRIPTION (provided by applicant): The liver is the main tissue site of vitamin A storage in the body and the hepatic stellate cell (HSC) (also referred to as Ito cell, fat-storing cell or lipocyte) is the major cellular site of vitamin A storage within the liver. Liver vitamin A stores serve as a buffer to prevent the adverse consequences of both insufficient and excessive dietary vitamin A intake. Nearly all hepatic vitamin A is found in the large cytoplasmic lipid droplets (LDs) present in HSCs. The number, size and vitamin A (retinyl ester) content of these LDs increases in response to greater dietary vitamin A intake and decreases in times of insufficient dietary intake. HSC LDs are a specialized subcellular organelle that has as its' only known physiologic function to facilitate vitamin A storage. This is unlike other hepatic LDs, for instance the LDs in hepatocytes, which have a more generalized role in neutral lipid (triglyceride and cholesterol) storage and metabolism. The relatively large retinyl ester content of HSC LDs and their responsiveness to dietary vitamin A intake render them very distinct from other LDs that are present in other cell types of the body. Yet little is known about the genesis or maintenance of HSC LDs or the biochemical and molecular events that are essential for this. Our studies will establish the biochemical and molecular processes that are essential for HSC LD formation and maintenance and how these are linked to vitamin A storage and mobilization from the liver. This project will address 3 fundamental questions regarding HSC LD biochemistry and vitamin A storage and metabolism in the liver. Aim 1 proposes characterization and study of the proteome of mouse HSC LDs in times of excessive, normal (control) or insufficient vitamin A dietary intake. The studies proposed in Aim 2 grow out of our published research showing that that mice lacking lecithin:retinol acyltransferase (LRAT), the enzyme responsible for retinyl ester formation in HSCs, also lack LDs in HSCs but not hepatocytes. This is very surprising since, for a rodent maintained on a control diet, retinyl ester accounts for less than 40% of the total lipid present in the droplets. In Aim 2 we propose to investigate why LRAT is needed for HSC LD formation. Finally, in Aim 3 we will investigate how vitamin A is mobilized from HSCs and whether this requires direct involvement of serum retinol-binding protein (RBP) synthesized in hepatocytes.