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（由申请人提供）：肝脏是体内维生素A的主要组织部位，肝脏中的储存和肝星状细胞（HSC）（HSC）（也称为ITO细胞，脂肪储存细胞或脂肪细胞）是主要的细胞部位维生素在肝内存储。肝脏维生素A商店是一种缓冲液，以防止摄入饮食中的维生素A摄入量不足和过多的不利后果。在HSC中存在的大细胞质脂质液滴（LDS）中，几乎所有肝脏维生素A都发现。这些LDS的数量，大小和维生素A（视乙烯基酯）含量增加，响应于饮食中的饮食中A的摄入量增加，并且在饮食摄入量不足的情况下会减少。 HSC LDS是一种专门的亚细胞细胞器，其唯一已知的生理功能可促进维生素A储存。这与其他肝LDS不同，例如肝细胞中的LDS，它们在中性脂质（甘油三酸酯和胆固醇）储存和代谢中具有更普遍的作用。 HSC LDS的视网膜酯含量相对较大及其对饮食维生素A摄入量的反应使它们与其他细胞类型中存在的LDS非常不同。然而，关于HSC LDS的起源或维持或生化和分子事件对此至关重要的知之甚少。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，以及它们与维生素A的储存和动员如何相关。该项目将解决有关HSC LD生物化学和维生素A的储存和代谢的3个基本问题。 AIM 1提出了在过度，正常（对照）或维生素不足的饮食摄入量的时间内对小鼠HSC LD的蛋白质组进行表征和研究。 AIM 2中提出的研究从我们发表的研究中得出，表明缺乏卵磷脂的小鼠：视黄醇酰基转移酶（LRAT）是HSC中负责视网膜酯形成的酶，在HSC中也缺乏LDS，但并非肝细胞。这是非常令人惊讶的，因为对于维持对照饮食的啮齿动物，视黄酯占液滴中脂质总脂质的40％。在AIM 2中，我们建议研究为什么HSC LD形成需要LRAT。最后，在AIM 3中，我们将研究如何从HSC中动员维生素A，以及这是否需要直接参与肝细胞中合成的血清视黄醇结合蛋白（RBP）。