Vitamin A Storage and Metabolism

维生素A的储存和代谢

• 批准号: 7660407
• 负责人: WILLIAM S BLANER
• 金额: $ 32.34万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660407
• 关键词: 5 year old; Accounting; Address; Adipocytes; Biochemical; Biochemistry; Buffers; Calories; Cell Nucleus; Cells; Characteristics; Cholesterol; Data; Diet; Dietary intake; Electrons; Enzymes; Esters; Event; Fatty acid glycerol esters; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Hypervitaminosis A; Impairment; Infant; Intake; Label; Link; Lipid Mobilization; Lipids; Literature; Liver; Maintenance; Metabolism; Molecular; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Nutritional status; Organelles; Phospholipids; Physiological; Plasma; Process; Proteins; Proteome; Proteomics; Public Health; Publishing; Rattus; Relative (related person); Reporting; Research; Research Personnel; Retinol Binding Proteins; Risk; Rodent; Role; Serum; Site; Source; Structure; Time; Tissues; Toxic effect; Triglycerides; UNICEF; Vitamin A; Vitamin A Deficiency; Vitamin Deficiency; Weight; World Health Organization; base; cell type; dietary supplements; insight; interest; lecithin-retinol acyltransferase; mortality; mutant mouse model; nutrition; prevent; response; retinyl esterase

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.

描述（申请人提供）：肝脏是体内维生素A储存的主要组织部位，肝星状细胞（HSC）（也称为伊藤细胞、脂肪储存细胞或脂细胞）是肝脏内维生素A储存的主要细胞部位。肝脏维生素 A 储存可作为缓冲剂，防止膳食维生素 A 摄入不足和过量造成的不良后果。几乎所有的肝脏维生素 A 都存在于 HSC 中的大细胞质脂滴 (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，并随着膳食维生素 A 摄入不足的时间而减少。 HSC LD 是一种特殊的亚细胞细胞器，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，后者在中性脂质（甘油三酯和胆固醇）储存和代谢中具有更广泛的作用。 HSC LD 的视黄酯含量相对较高，而且它们对膳食维生素 A 摄入量的反应性使它们与体内其他细胞类型中存在的其他 LD 非常不同。然而，人们对 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 HSC LD 形成和维持所必需的生化和分子过程，以及这些过程与肝脏中维生素 A 储存和动员的关系。该项目将解决有关 HSC LD 生物化学以及肝脏中维生素 A 储存和代谢的 3 个基本问题。目标 1 建议对维生素 A 饮食摄入过量、正常（对照）或不足时小鼠 HSC LD 的蛋白质组进行表征和研究。目标 2 中提出的研究源于我们已发表的研究，该研究表明，缺乏卵磷脂：视黄醇酰基转移酶 (LRAT)（负责 HSC 中视黄酯形成的酶）的小鼠，在 HSC 中也缺乏 LD，但在肝细胞中则不然。这是非常令人惊讶的，因为对于维持对照饮食的啮齿动物来说，视黄酯占液滴中存在的总脂质的不到40%。在目标 2 中，我们建议研究为什么 LRAT 是 HSC LD 形成所必需的。最后，在目标 3 中，我们将研究如何从 HSC 中动员维生素 A，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。