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）：世界卫生组织于2004年出版的长期饮酒率估算的估计值表明，酒精每年约为180万死亡。饮酒会导致体内几乎每个器官的成瘾和损害。基于酒精相关疾病的分子事件是复杂的，尚未完全理解。类维生素A及其代谢产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。酒精的一种不利作用涉及促进组织和器官损伤，通过损害类维生素类似的代谢和肝脏作用（存储了70％的人类类维生素类似）和外周组织中的作用。酗酒者通常的肝和类维生素类样水平降低。这会导致维持正常细胞增殖和分化的类视感上的可用性降低，使细胞/组织更容易受到酒精诱导的损伤。 文献中提出的原因是解释了为什么在酒精中毒中受损类维生素性稳态的原因是：1。酗酒抑制了通过竞争酗酒（视乙醇）脱氢酶和Aldheyde（视网膜）（视网膜）（视网膜）（视网膜）脱氢酶催化视网膜酸综合的饮酒（视网膜）脱氢酶和甲基脱氢酶（视网膜）脱氢酶（视网膜）脱氢酶（视网膜）脱氢酶的合成； 2。酒精会加速性类维生素性氧化，涉及乙醇诱导的细胞色素（如CYP2E1）；和3。酒精增加了从肝脏到其他组织中储存的类维生素类动物的动员。目前，在类维生素性代谢领域工作的研究人员认为，调节细胞/组织中类维生素性稳态的主要代谢事件是视网膜酯的合成（卵磷脂：视黄醇酰基转移酶或LRAT）和视网膜酸性氧化（通过细胞染色体的催化剂）。进一步认为，肝类维生素性代谢与周围组织的代谢是通过视黄醇结合蛋白（RBP）快速地介导的乙醇间介导的。我们的调查将重点放在肝类视黄素的储存和类维生素性动员/重新分布肝脏以及这些重要的调节过程如何受到慢性酒精摄入的影响。我们将仅在骨骼肌（MCK-LPL0小鼠）中使用LRAT - / - 和RBP - / - 小鼠和表达脂蛋白脂肪酶（LPL）的小鼠来研究这些关系。我们已经研究并发表了有关这些小鼠的特征的描述，该特征是关于类维生素性储存，代谢和运输的，现在建议使用这些小鼠模型来研究酒精诱导的器官损伤。 LRAT是组织/细胞类维生素性稳态的中心调节剂，可控制视黄醇合成的视黄醇可用性。 LRAT - / - 小鼠在任何组织中储存的视黄量很少，在肝脏中都没有。 RBP主要由肝脏合成，是循环中视黄醇的唯一转运蛋白，占禁食循环中存在的类视黄素的95％。 RBP - / - 小鼠通常在肝脏中积累饮食性类维生素类似，并且在维持性类维生素性饮食中保持表型正常。但是，RBP - / - 小鼠无法动员/从肝脏重新分布视黄醇。 LPL催化视黄酯的水解，其表达在活化的肝星状细胞（HSC）（HSC）的30倍以上升高，这是肝脏中视网膜类似储存的细胞位点。已经提出，LPL在HSC激活后促进了HSC类维生素类动物储存的视网膜样动员。在健康的MCK-LPL0小鼠中，肝类视黄素的储存和动员正常，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类视丁素水平没有差异。因此，使用无法在活化的HSC中表达LPL的MCK-LPL0小鼠，我们将能够在酒精诱导的肝病中定义LPL的作用。 该项目由2个目标组成。在AIM 1中，我们会问：缺乏肝类维生素店如何影响酒精引起的肝病发展和肝脏再生？这些研究将涉及使用LRAT - / - 小鼠探索肝类视黄素储存和LRAT在酒精性肝病发展中的作用。在AIM 2中，我们会问：将动员/重新分配肝类视黄素存储的能力是否有助于酒精引起的组织/器官损伤的发展？在这里，我们将采用无法动员肝类视网膜化储物的RBP - / - 小鼠，而MCK-LPL0小鼠无法在肝脏中表达LPL，这是一种肝脏，该器官在肝脏中提出了作用，在动员肝视网膜视网膜酯商店中起作用受伤。我们还将在WT，RBP - / - 和MCK-LPL0小鼠中探索是否动员/重新分配肝性维生素储存的能力有助于外周器官损伤的发展，特别是对酒精性心肌病的发展。 公共卫生相关性：长期饮酒是一个主要的公共卫生问题，导致体内几乎每个器官的成瘾和损害。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，尤其是肝脏，其中70％的维生素A存储在体内。这导致维生素可用于维持正常细胞增殖，分化和肝脏中的凋亡。我们提出的研究将对饮酒，维生素A代谢和作用以及酒精器官损害之间的关系有更全面的了解。