Retinoid Metabolism and Alcohol Induced Disease

类维生素A代谢和酒精诱发的疾病

• 批准号: 7944057
• 负责人: WILLIAM S BLANER
• 金额: $ 89.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944057
• 关键词: 11 cis Retinal; Accounting; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Cardiomyopathy; Alcoholic Liver Diseases; Alcohols; All-Trans-Retinol; Apoptosis; Area; Binding; Biology; Blood; Blood Circulation; Cardiac; Carotene; Carrier Proteins; Cell Proliferation; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Complex; Cytochromes; Death Rate; Development; Diet; Disease; Enzymes; Esters; Ethanol; Ethanol Metabolism; Etiology; Event; Fasting; Gene Expression; Genes; Hepatic; Hepatic Stellate Cell; Hepatic Tissue; Homeostasis; Hydrolysis; Hypertension; Injury; Investigation; Isotretinoin; Ligands; Lipids; Literature; Liver; Liver Regeneration; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Mus; Normal Cell; Organ; Peripheral; Platelet Factor 4; Play; Process; Public Health; Publishing; RXR; Regulation; Research Personnel; Retinal; Retinal dehydrogenase; Retinoic Acid Receptor; Retinoids; Retinol Binding Proteins; Retinol dehydrogenase; Rhodopsin; Role; Scheme; Serum; Site; Skeletal Muscle; Stroke; Tissues; Tretinoin; Vision; Vitamin A; Wild Type Mouse; Work; World Health Organization; addiction; alitretinoin; chromophore; chronic alcohol ingestion; feeding; lecithin-retinol acyltransferase; lipoprotein lipase; mouse model; mutant mouse model; oxidation; problem drinker; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Estimates of death rates caused by chronic alcohol consumption, published in 2004 by the World Health Organization, indicate that alcohol accounts for approximately 1.8 million deaths per year. Alcohol consumption leads to addiction and damage to almost every organ in the body. The molecular events that underlie alcohol-associated disease are complex and not completely understood. Retinoids (vitamin A and its metabolites) are potent transcriptional regulators that are needed for mediating normal cell proliferation, differentiation and apoptosis. One adverse action of alcohol involves promotion of tissue and organ damage by impairing retinoid metabolism and actions in liver (where 70% of the body's retinoid is stored) and in peripheral tissues. Alcoholics generally have very reduced hepatic and tissue retinoid levels. This results in decreased retinoid availability for maintaining normal cell proliferation and differentiation, rendering cells/tissues more susceptible to alcohol-induced injury. Reasons proposed in the literature to explain why retinoid homeostasis is impaired in alcoholics are: 1. alcohol inhibits the synthesis of the transcriptionally active retinoid, retinoic acid, by competing for alcohol (retinol) dehydrogenases and aldheyde (retinal) dehydrogenases catalyzing retinoic acid synthesis; 2. alcohol accelerates retinoid oxidation, involving ethanol-inducible cytochromes like Cyp2E1; and 3. alcohol increases mobilization of stored retinoid from the liver to other tissues. It is currently believed by investigators working in the area of retinoid metabolism that the key metabolic events regulating retinoid homeostasis within cells/tissues are retinyl ester synthesis (involving lecithin:retinol acyltransferase or LRAT) and retinoic acid oxidation (catalyzed by cytochrome enzymes). It is further thought that hepatic retinoid metabolism is integrated with that of peripheral tissues, through rapid interorgan transfer of retinol mediate via retinol-binding protein (RBP). Our investigations will focus on hepatic retinoid storage and retinoid mobilization/redistribution from the liver and how these important regulatory processes are influenced by chronic alcohol intake. We will employ Lrat-/- and Rbp-/- mice and mice expressing lipoprotein lipase (LpL) solely in skeletal muscle (MCK-LpL0 mice) to investigate these relationships. We have studied and published descriptions of the characteristics of these mice with regards to retinoid storage, metabolism and transport and now propose to employ these mouse models to study alcohol-induced organ injury. LRAT is a central regulator of tissue/cellular retinoid homeostasis, controlling retinol availability for retinoic acid synthesis. Lrat-/- mice possess very little stored retinoid in any tissue, and none in liver. RBP is synthesized primarily by the liver and is the sole transport protein for retinol in the circulation, accounting for > 95% of the retinoid present in the fasting circulation. Rbp-/- mice accumulate dietary retinoid normally in liver and are phenotypically normal when maintained on a retinoid-sufficient diet. However Rbp-/- mice are unable to mobilize/redistribute retinol from the liver to the periphery. LpL catalyzes the hydrolysis of retinyl esters and its expression is elevated over 30-fold in activated hepatic stellate cells (HSCs), the cellular site of retinoid storage in the liver. It has been proposed that LpL facilitates retinoid mobilization from HSC retinoid stores upon HSC activation. Hepatic retinoid storage and mobilization are normal in healthy MCK-LpL0 mice since serum and hepatic retinoid levels are not different for these mice compared to matched chow fed wild type (WT) mice. Thus, using MCK-LpL0 mice which are unable to express LpL in activated HSCs, we will be able to define a role for LpL in alcohol-induced liver disease. The project consists of 2 Aims. In Aim 1 we will ask: How does the absence of hepatic retinoid stores influence alcohol-induced liver disease development and liver regeneration? These investigations will involve the use of Lrat-/- mice to explore the role that hepatic retinoid stores and LRAT have in the development of alcoholic liver disease. In Aim 2 we will ask: Does the ability to mobilize/redistribute hepatic retinoid stores to the periphery contribute to the development of alcohol-induced tissue/organ injury? Here we will employ Rbp-/- mice, which are unable to mobilize hepatic retinoid stores, and MCK-LpL0 mice which can not express LpL in liver, an organ where it is proposed LpL plays a role in mobilizing hepatic retinyl ester stores upon hepatic injury. We will also explore in WT, Rbp-/- and MCK-LpL0 mice whether the ability to mobilize/redistribute hepatic retinoid stores contributes to the development of peripheral organ injury, specifically to alcoholic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Chronic alcohol consumption is a major public health problem, leading to addiction and damage of almost every organ in the body. There is compelling evidence that alcohol impairs vitamin A metabolism in tissues, especially liver, where 70% of the vitamin A present in the body is stored. This results in lessened vitamin A availability for maintaining normal cellular proliferation, differentiation and apoptosis in liver and other organs. We are proposing studies that will provide a more complete understanding of relationships between alcohol consumption, vitamin A metabolism and actions, and alcoholic organ damage.

描述（由申请人提供）：世界卫生组织 2004 年公布的对长期饮酒造成的死亡率的估计表明，每年约有 180 万人因酒精死亡。饮酒会导致成瘾并损害身体的几乎每个器官。酒精相关疾病的分子事件很复杂，目前尚未完全了解。类维生素A（维生素A及其代谢物）是介导正常细胞增殖、分化和凋亡所需的有效转录调节剂。酒精的一种不良作用是通过损害类视黄醇代谢以及肝脏（体内储存有 70% 的类视黄醇）和周围组织的作用，从而促进组织和器官损伤。酗酒者的肝脏和组织中的类维生素A水平通常非常低。这导致维持正常细胞增殖和分化的类维生素A可用性降低，使细胞/组织更容易受到酒精引起的损伤。 文献中提出的解释为什么酗酒者的类视黄醇稳态受损的原因是： 1. 酒精通过竞争催化视黄酸合成的醇（视黄醇）脱氢酶和醛（视黄醛）脱氢酶来抑制转录活性类视黄醇、视黄酸的合成； 2. 酒精加速类维生素A氧化，涉及乙醇诱导的细胞色素，如Cyp2E1； 3.酒精会增加储存的类视黄醇从肝脏到其他组织的动员。目前，类视黄醇代谢领域的研究人员认为，调节细胞/组织内类视黄醇稳态的关键代谢事件是视黄酯合成（涉及卵磷脂：视黄醇酰基转移酶或LRAT）和视黄酸氧化（由细胞色素酶催化）。进一步认为，通过视黄醇结合蛋白（RBP）介导的视黄醇快速器官间转移，肝脏类视黄醇代谢与外周组织的代谢整合。我们的研究将集中于肝脏类视黄醇的储存和肝脏中类视黄醇的动员/再分配，以及这些重要的调节过程如何受到长期酒精摄入的影响。我们将使用 Lrat-/- 和 Rbp-/- 小鼠以及仅在骨骼肌中表达脂蛋白脂肪酶 (LpL) 的小鼠（MCK-LpL0 小鼠）来研究这些关系。我们已经研究并发表了这些小鼠在类维生素A储存、代谢和运输方面的特征的描述，现在建议利用这些小鼠模型来研究酒精引起的器官损伤。 LRAT 是组织/细胞类视黄醇稳态的中央调节剂，控制视黄醇用于视黄酸合成的可用性。 Lrat-/-小鼠的任何组织中几乎没有储存类维生素A，肝脏中也没有。 RBP 主要由肝脏合成，是循环中视黄醇的唯一转运蛋白，占空腹循环中存在的类视黄醇的 95% 以上。 Rbp-/- 小鼠的膳食类视黄醇在肝脏中正常积累，并且在维持足够的类视黄醇饮食时表型正常。然而，Rbp-/- 小鼠无法将视黄醇从肝脏动员/重新分配到外周。 LpL 催化视黄酯的水解，其表达在活化的肝星状细胞 (HSC) 中升高超过 30 倍，HSC 是肝脏中类视黄醇储存的细胞部位。有人提出，在 HSC 激活后，LpL 促进 HSC 类视黄醇储存中的类视黄醇动员。健康 MCK-LpL0 小鼠的肝脏类维生素A储存和动员是正常的，因为与匹配的食物喂养的野生型（WT）小鼠相比，这些小鼠的血清和肝脏类维生素A水平没有差异。因此，使用无法在活化的 HSC 中表达 LpL 的 MCK-LpL0 小鼠，我们将能够定义 LpL 在酒精性肝病中的作用。 该项目由 2 个目标组成。在目标 1 中，我们会问：肝脏类视黄醇储备的缺失如何影响酒精诱发的肝病发展和肝再生？这些研究将涉及使用 Lrat-/- 小鼠来探索肝脏类维生素A储存和 LRAT 在酒精性肝病发展中的作用。在目标 2 中，我们会问：动员/重新分配肝脏类视黄醇储备至外周的能力是否会导致酒精引起的组织/器官损伤的发生？在这里，我们将使用无法调动肝脏类视黄醇储存的 Rbp-/- 小鼠，以及不能在肝脏中表达 LpL 的 MCK-LpL0 小鼠，其中 LpL 在肝脏中发挥着调动肝脏视黄酯储存的作用。受伤。我们还将在 WT、Rbp-/- 和 MCK-LpL0 小鼠中探讨动员/重新分配肝脏类视黄醇储备的能力是否会导致外周器官损伤，特别是酒精性心肌病的发生。 公共健康相关性：长期饮酒是一个主要的公共健康问题，导致成瘾和身体几乎每个器官的损伤。有令人信服的证据表明，酒精会损害组织中的维生素 A 代谢，尤其是肝脏，体内 70% 的维生素 A 都储存在肝脏中。这导致维持肝脏和其他器官正常细胞增殖、分化和凋亡的维生素 A 可用性减少。我们提出的研究将更全面地了解饮酒、维生素 A 代谢和作用以及酒精性器官损伤之间的关系。