REGULATION OF HEPATIC RETINOL METABOLISM

肝脏视黄醇代谢的调节

• 批准号: 2146139
• 负责人: A. CATHARINE ROSS
• 金额: $ 13.68万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2146139
• 关键词: SDS polyacrylamide gel electrophoresis; acyltransferase; all trans retinol; antineoplastics; dietary supplements; enzyme activity; enzyme structure; esterification; genetic transcription; genetic translation; isolation perfusion; laboratory rat; liver cells; liver metabolism; microsomes; northern blottings; nutrient requirement; nutrition related tag; oxidation; retinoid binding proteins; retinoids; vitamin A deficiency

The major objective of this research plan is to understand how exogenous retinoids, principally retinoic acid (RA) and 4-hydroxyphenyl retinamide (4-HPR), influence the hepatic metabolism of retinol. Hepatic retinol may potentially follow three main metabolic pathways: esterification with long-chain fatty acids to form retinyl esters, a reversible storage process; exit from the cell into plasma in association with retinol- binding protein (RBP); or oxidation leading to retinaldehyde and then RA, an irreversible activation or degradative process. The regulatory mechanisms that serve to partition retinol among these different pathways are largely unknown. New information has demonstrated the importance of the cellular retinoid-binding proteins in directing retinoids to specific enzymes. Retinol bound to the cellular retinol-binding protein, GRBP, is available for esterification by the microsomal enzyme lecithin: retinol acyltransferase (LRAT) and has also been shown to be the substrate of a microsomal retinol dehydrogenase. Recently, we have shown that liver LRAT activity is strongly regulated by vitamin A nutritional status. In the proposed research we will address 7 specific aims concerning hepatic retinol metabolism. In particular, we will examine how it is regulated by changes in vitamin A nutritional status and by exogenous retinoids with anti-cancer activity. One such retinoid, 4-HPR, has been shown to inhibit carcinogenesis and to be relatively non-toxic but it causes a marked suppression of plasma retinol and RBP. The mechanism of this decrease is not known. The first R aims examine the regulation of microsomal LRAT while Aims 5 and 6 address the synthesis of RBP and the oxidation of retinol, respectively. In Aim 1 we will determine which retinoids besides RA can regulate LRAT activity. The goal of Aim 2 is to test the hypothesis that there is competition between LRAT and the RBP secretion pathway for retinol. We will examine whether induction of LRAT by retinoids such as 4-HPR reduces the availability of retinol for secretion on RBP. In Aim 3 we will determine the cellular distribution of LRAT between parenchymal and nonparenchymal cells. In Aim 4 we will use the technique of radiation inactivation to explore the properties of LRAT in liver and intestinal microsomes and extracts. The goal of Aim 5, which complements Aim 2, is to determine whether RA or 4-HPR acts as a signal to regulate the transcription or translation of RBP. In Aim 6, we will test the hypothesis that oxidation of CRBP-bound retinol by microsomal retinol dehydrogenase is increased after treatment with RA or 4-HPR. The proposed research is relevant to understanding the normal feedback regulation of retinol metabolism by endogenously-produced RA as well as the influence of retinoids used in cancer chemoprevention, such as RA and 4-HPR,on the metabolism of retinol and the dietary requirement for vitamin A.

该研究计划的主要目标是了解外生因素如何 类视黄醇，主要是视黄酸 (RA) 和 4-羟基苯基视黄酰胺 (4-HPR)，影响视黄醇的肝脏代谢。肝脏视黄醇可能 可能遵循三个主要代谢途径： 长链脂肪酸形成视黄酯，可逆储存 过程;与视黄醇结合从细胞进入血浆 结合蛋白（RBP）；或氧化导致视黄醛然后RA， 不可逆的激活或降解过程。监管 在这些不同途径之间分配视黄醇的机制 很大程度上是未知的。新信息表明了重要性 细胞视黄醇结合蛋白将视黄醇导向特定的 酶。 视黄醇与细胞视黄醇结合蛋白 GRBP 结合， 可通过微粒体酶卵磷脂酯化：视黄醇 酰基转移酶 (LRAT) 也已被证明是 微粒体视黄醇脱氢酶。最近，我们发现肝脏 LRAT 活性很大程度上受维生素 A 营养状况的调节。在 拟议的研究我们将解决有关肝脏的 7 个具体目标 视黄醇代谢。 特别是，我们将研究它是如何监管的 维生素A营养状况的变化和外源性维A酸的影响 抗癌活性。 一种这样的类维生素A，4-HPR，已被证明可以抑制 致癌且相对无毒，但会引起显着的致癌作用 抑制血浆视黄醇和 RBP。 这种减少的机制是 不知道。第一个 R 旨在检查微粒体 LRAT 的调节 而目标 5 和 6 则涉及 RBP 的合成和 分别是视黄醇。在目标 1 中，我们将确定除 RA可以调节LRAT活性。目标 2 的目标是检验假设 LRAT 和 RBP 分泌途径之间存在竞争 视黄醇。 我们将检查类视黄醇是否诱导 LRAT，例如 4-HPR 降低了 RBP 上分泌视黄醇的可用性。目标 3 我们将确定 LRAT 在实质细胞之间的细胞分布 和非实质细胞。 在目标 4 中，我们将使用辐射技术 灭活以探索 LRAT 在肝脏和肠道中的特性 微粒体和提取物。 目标 5 的目标补充了 目标 2 是确定 RA 或 4-HPR 是否充当信号 调节 RBP 的转录或翻译。 在目标 6 中，我们将测试 微粒体视黄醇氧化 CRBP 结合视黄醇的假设 用 RA 或 4-HPR 治疗后脱氢酶增加。 拟议的 研究与理解正常的反馈调节有关 内源性 RA 的视黄醇代谢以及 用于癌症化学预防的类视黄醇，例如 RA 和 4-HPR 视黄醇的代谢和维生素 A 的饮食需求。