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

• 批准号: 10397177
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397177
• 关键词: Affect; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Animal Model; Benign; Betaine; Biogenesis; Characteristics; Cirrhosis; Complement; Consumption; Data; Development; 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; 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; dietary; fatty liver disease; insight; methyl group; monolayer; non-alcoholic fatty liver disease; novel; prevent; problem drinker; targeted treatment; treatment strategy; Affect; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Animal Model; Benign; Betaine; Biogenesis; Characteristics; Cirrhosis; Complement; Consumption; Data; Development; 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; 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; dietary; fatty liver disease; insight; methyl group; monolayer; non-alcoholic fatty liver disease; novel; prevent; problem drinker; targeted treatment; treatment strategy

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.

项目摘要/摘要 脂肪肝（脂肪变性）的发展是酒精性肝病（ALD）的早期表现，可以 继续滥用酒精性肝炎和肝硬化。肝脂肪变性是可逆的 因此，ALD的早期阶段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发展的机制和（ii）制定策略 具有相似组织病理学和进展史的该和其他脂肪肝疾病的治疗/预防。 我们先前表明，磷脂酰乙醇胺甲基转移酶（PEMT）的减少损害 非常低密度的脂蛋白（VLDL）分泌，导致酒精脂肪变性。 PEMT催化 磷脂酰乙醇胺（PE）的甲基化以产生磷脂酰胆碱（PC），这是必要的 正常的VLDL组装和分泌。我们进一步表明，用甲基捐献者Betaine治疗， 将PEMT催化的PC合成归一化，以促进VLDL分泌并防止酒精脂肪变性。 已经证明肝细胞质脂质液滴（LDS）在VLDL中起着不可或缺的作用 生物发生。这是因为VLDL组件受这些LDS中存储的甘油三酸酯的可用性调节 必须将其水解以提供VLDL组件的底物。 LD被一个单层包围 磷脂； PC是最丰富的课程，其次是PE和其他类别。此外，蛋白质的轨道 确定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脂解会导致肝脂肪变性的发展。我们建议乙醇 - PEMT催化PC的诱导损伤降低了LD单层中的PC：PE比。这促进了 在与LD相关蛋白的补体中产生扩大的LDS。这些 变化共同影响LD甘油三酸酯存储的脂解，破坏了组装和分泌 VLDL导致肝脏脂肪变性。我们进一步假设饮食中补充饮食逆转 通过标准化LD PC：PE比和VLDL生物发生，酒精脂肪变性。 为了检验我们的假设，我们提出以下特定目的： 特定目标1：表征乙醇如何改变肝LDS的磷脂和蛋白质组成。 特定目的2：检查酒精对LD脂解的影响动员甘油三酸酯商店 VLDL分泌。 特定目的3：确定甜菜碱对酒精诱导的LD动力学改变的影响。 这些研究的完成将洞悉维持基本甲基化的重要性 通过PEMT催化的反应在调节脂质液滴的动力学方面催化并防止 酒精脂肪变性和其他慢性肝病，包括非酒精性肝病。