Impaired phospholipid methylation results in decreased lipid droplet lipolysis: Role in hepatic steatosis

磷脂甲基化受损导致脂滴脂肪分解减少：在肝脂肪变性中的作用

基本信息

批准号：
9900698
负责人：
Kusum K. Kharbanda
金额：
$ 31.46万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-05 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900698
关键词：
Affect Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Animal Model Benign Betaine Bioavailable Biogenesis Characteristics Cirrhosis Complement Consumption Data Development Diet Digestion Disease Progression Economic Burden Enzymes Ethanol Fatty Liver Fatty acid glycerol esters Fibrosis Generations Healthcare Systems Hepatic Hepatocyte Histopathology Impairment Investigation Lecithin Lipase Lipid Binding Lipids Lipolysis Liver Liver diseases Malignant Neoplasms Mediating Membrane Proteins Metabolic Methylation Modeling Nutrient Ocular orbit Organelles Phosphatidylethanolamine Phosphatidylethanolamine N-Methyltransferase Phospholipids Play Prevention Proteins Reaction Recording of previous events Reporting Resistance Role Structure Supplementation Surface Testing Therapeutic Intervention Triglycerides Very low density lipoprotein alcohol effect alcohol exposure alcohol misuse alcohol use initiation base betaine-homocysteine methyltransferase chronic liver disease insight methyl group monolayer non-alcoholic fatty liver disease novel prevent problem drinker targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The development of fatty liver (steatosis) is an early manifestation of alcoholic liver disease (ALD) that can progress to alcoholic hepatitis and cirrhosis with continued alcohol misuse. Hepatic steatosis is a reversible early stage of ALD and is, therefore, a prime target for therapeutic intervention. Our long term objectives are to (i) understand the mechanisms of alcoholic steatosis development and (ii) formulate strategies for treatment/prevention of this and other fatty liver diseases with similar histopathology and progression history. We have previously shown that reduction in phosphatidylethanolamine methyltransferase (PEMT) impairs very-low-density lipoproteins (VLDL) secretion contributing to alcoholic steatosis. PEMT catalyzes the methylation of phosphatidylethanolamine (PE) to generate phosphatidylcholine (PC), which is necessary for normal VLDL assembly and secretion. We have further shown that treatment with betaine, a methyl donor, normalizes PEMT-catalyzed PC synthesis to promote VLDL secretion and prevent alcoholic steatosis. It has been demonstrated that hepatic cytoplasmic lipid droplets (LDs) play an integral role in VLDL biogenesis. This is because VLDL assembly is regulated by the availability of triglycerides stored in these LDs which have to be hydrolyzed to provide substrates for VLDL assembly. LDs are surrounded by a monolayer of phospholipids; PC is the most abundant class followed by PE and others. Further, an orbit of proteins determines the metabolic fate of LD lipid stores. Based on these considerations, we present a novel hypothesis that impaired phospholipid methylation contributes to the development of hepatic steatosis by impairing LD lipolysis. We propose that the ethanol- induced impairment in PEMT-catalyzed PC decreases the PC:PE ratio in the LD monolayer. This promotes generation of enlarged LDs with significant alterations in the complement of LD-associated proteins. These changes together affect the lipolysis of the LD triglyceride stores disrupting the assembly and secretion of VLDL resulting in liver steatosis. We further hypothesize that dietary betaine supplementation reverses alcoholic steatosis by normalizing LD PC:PE ratio and VLDL biogenesis. To test our hypothesis, we propose the following Specific Aims: Specific Aim 1: To characterize how ethanol alters the phospholipid and protein composition of hepatic LDs. Specific Aim 2: To examine the effect of alcohol on LD lipolysis for mobilization of triglyceride stores for VLDL secretion. Specific Aim 3: To determine the effects of betaine on alcohol-induced alterations in LD dynamics. Completion of these studies will provide insight into the importance of maintaining the essential methylation reaction catalyzed by PEMT in regulating the dynamics of lipid droplet and preventing the development of alcoholic steatosis and other chronic liver diseases including non-alcoholic liver disease.

项目概要/摘要脂肪肝（脂肪变性）是酒精性肝病 (ALD) 的早期表现，可导致持续滥用酒精会导致酒精性肝炎和肝硬化。肝脂肪变性是可逆的 ALD 的早期阶段，因此是治疗干预的主要目标。我们的长期目标是 (i) 了解酒精性脂肪变性的发展机制并 (ii) 制定策略治疗/预防这种疾病以及具有相似组织病理学和进展史的其他脂肪肝疾病。我们之前已经表明，磷脂酰乙醇胺甲基转移酶（PEMT）的减少会损害极低密度脂蛋白（VLDL）分泌导致酒精性脂肪变性。 PEMT 催化磷脂酰乙醇胺 (PE) 甲基化生成磷脂酰胆碱 (PC)，这是正常的 VLDL 组装和分泌。我们进一步表明，用甲基供体甜菜碱处理，使 PEMT 催化的 PC 合成正常化，促进 VLDL 分泌并预防酒精性脂肪变性。已证明肝细胞质脂滴 (LD) 在 VLDL 中发挥着不可或缺的作用生物发生。这是因为 VLDL 的组装受到这些 LD 中存储的甘油三酯的可用性的调节必须水解才能为 VLDL 组装提供底物。 LD 被单层包围磷脂； PC 是最丰富的类别，其次是 PE 等。此外，蛋白质的轨道决定 LD 脂质储存的代谢命运。基于这些考虑，我们提出了一个新的假设，即磷脂甲基化受损通过损害 LD 脂肪分解，促进肝脂肪变性的发展。我们建议乙醇- PEMT 催化的 PC 中诱导的损伤降低了 LD 单层中的 PC:PE 比率。这促进了产生扩大的 LD，并且 LD 相关蛋白的补体发生显着改变。这些这些变化共同影响 LD 甘油三酯储存的脂解作用，破坏 LD 甘油三酯的组装和分泌 VLDL导致肝脏脂肪变性。我们进一步假设饮食中补充甜菜碱可以逆转通过使 LD PC:PE 比率和 VLDL 生物发生正常化来治疗酒精性脂肪变性。为了检验我们的假设，我们提出以下具体目标：具体目标 1：表征乙醇如何改变肝脏 LD 的磷脂和蛋白质组成。具体目标 2：检查酒精对 LD 脂肪分解的影响，以动员甘油三酯储存极低密度脂蛋白的分泌。具体目标 3：确定甜菜碱对酒精引起的 LD 动态变化的影响。完成这些研究将深入了解维持必需甲基化的重要性 PEMT 催化反应调节脂滴动力学并防止酒精性脂肪变性和其他慢性肝病，包括非酒精性肝病。