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的是了解外源 视视视网膜类动物，主要是视黄酸（RA）和4-羟基苯基视网膜酰胺 （4-hpr），影响视黄醇的肝代谢。肝视黄醇可能 可能遵循三种主要代谢途径：酯化 长链脂肪酸形成视黄酯，可逆储存 过程;与视黄醇相关的细胞退出进入血浆 结合蛋白（RBP）；或氧化导致视网膜醛，然后是RA， 不可逆的激活或降解过程。监管 这些不同途径之间的视黄醇的机制 在很大程度上未知。新信息表明了 细胞类维生素性结合蛋白将类维生素类似于特定 酶。 视黄醇结合到细胞视黄醇结合蛋白GRBP为 可通过微粒体酶卵磷脂酯化：视黄醇 酰基转移酶（LRAT），也已证明是A的底物 微粒体视黄醇脱氢酶。最近，我们已经证明了肝脏LRAT 活性受维生素A营养状况的强烈调节。在 拟议的研究我们将解决有关肝的7个具体目标 视网膜代谢。 特别是，我们将研究它如何受到 维生素A营养状况和外源性类维生素的变化 抗癌活性。 一种这样的类维生素类似于4-HPR，已证明可以抑制 癌变和相对无毒，但会引起明显的 血浆视网膜和RBP的抑制。 这种减少的机制是 不知道。第一个R的目的检查微粒体LRAT的调节 而目标5和6解决了RBP的合成和氧化的氧化。 视网膜分别。在AIM 1中，我们将确定除了哪些类视黄素 RA可以调节LRAT活性。目标2的目的是检验假设 LRAT与RBP分泌途径之间的竞争 视网膜。 我们将检查性类维生素的诱导LRAT（例如 4-HPR降低了视黄醇在RBP上分泌的可用性。在目标3中 我们将确定实质之间LRAT的细胞分布 和非实质细胞。 在AIM 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。 AIM 5的目标，该目标是补充 AIM 2是确定RA或4-HPR是否充当信号 调节RBP的转录或翻译。 在AIM 6中，我们将测试 微粒体视黄醇对CRBP结合视黄醇氧化的假设 用RA或4-HPR处理后，脱氢酶增加。 提议 研究与了解正常的反馈调节有关 视黄醇代谢由内生生产的RA以及影响 在癌症化学预防中使用的类视网膜类似，例如RA和4-HPR 视黄醇的代谢和维生素A的饮食需求。