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年公布的慢性酒精消费造成的死亡率估计数表明，每年约有180万人死于酒精。饮酒会导致上瘾，并损害身体几乎所有器官。酒精相关疾病的分子基础是复杂的，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。酒精的一个不利作用涉及通过损害类维生素A代谢和肝脏（其中储存了身体的70%的类维生素A）和外周组织中的作用来促进组织和器官损伤。酗酒者通常肝脏和组织中的类维生素A水平非常低。这导致用于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诱导的损伤。 文献中提出的解释酗酒者维甲酸稳态受损的原因是：1。酒精通过竞争催化视黄酸合成的酒精（视黄醇）脱氢酶和醛（视网膜）脱氢酶来抑制转录活性类维生素A、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Cyp 2 E1;和3.酒精增加了储存的类维生素A从肝脏向其它组织的移动。目前，在类维生素A代谢领域工作的研究人员认为，调节细胞/组织内类维生素A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）介导的视黄醇的快速器官间转移，肝脏类维生素A代谢与外周组织的代谢相结合。我们的调查将集中在肝脏类维生素A的存储和类维生素A动员/重新分配从肝脏和这些重要的调节过程是如何影响慢性酒精摄入量。我们将采用Lrat-/-和Rbp-/-小鼠和仅在骨骼肌中表达脂蛋白脂酶（LpL）的小鼠（MCK-LpL 0小鼠）来研究这些关系。我们已经研究并发表了这些小鼠关于维甲酸储存，代谢和运输的特征的描述，现在建议采用这些小鼠模型来研究酒精诱导的器官损伤。LRAT是组织/细胞类维生素A稳态的中心调节剂，控制视黄酸合成的视黄醇可用性。Lrat-/-小鼠在任何组织中具有非常少的储存类维生素A，并且在肝脏中没有。RBP主要由肝脏合成，并且是循环中视黄醇的唯一转运蛋白，占空腹循环中存在的类维生素A的> 95%。Rbp-/-小鼠通常在肝脏中积累膳食类维生素A，并且当维持类维生素A充足的饮食时，其表型正常。然而，Rbp-/-小鼠不能将视黄醇从肝脏动员/重新分布到外周。LpL催化视黄酯的水解，并且其表达在活化的肝星状细胞（HSC）中升高超过30倍，所述肝星状细胞是肝脏中类维生素A储存的细胞位点。已经提出，LpL在HSC活化时促进类维生素A从HSC类维生素A库的动员。在健康MCK-LpL 0小鼠中，肝脏类维生素A储存和动员是正常的，因为这些小鼠的血清和肝脏类维生素A水平与匹配的饲料喂养的野生型（WT）小鼠相比没有差异。因此，使用MCK-LpL 0小鼠不能在活化的HSC中表达LpL，我们将能够确定LpL在酒精诱导的肝病中的作用。 该项目包括两个目标。在目标1中，我们将问：肝脏类维生素A储存的缺乏如何影响酒精诱导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：调动/重新分配肝脏维甲酸储存到外周的能力是否有助于酒精诱导的组织/器官损伤的发展？在这里，我们将采用Rbp-/-小鼠，这是不能动员肝脏类维生素A储存，和MCK-LpL 0小鼠，不能表达LpL在肝脏，一个器官，它提出了LpL在动员肝脏视黄酯储存肝损伤后的作用。我们还将在WT、Rbp-/-和MCK-LpL 0小鼠中探索动员/重新分配肝脏类维生素A储存的能力是否有助于外周器官损伤的发展，特别是酒精性心肌病。 公共卫生相关性：长期饮酒是一个重大的公共卫生问题，导致成瘾和身体几乎每个器官的损害。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，特别是肝脏，其中储存了体内70%的维生素A。这导致减少维生素A的可用性，以维持肝脏和其他器官中的正常细胞增殖、分化和凋亡。我们建议进行研究，以更全面地了解酒精消费、维生素A代谢和行动以及酒精性器官损伤之间的关系。