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

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.

项目总结/摘要 脂肪肝（脂肪变性）的发展是酒精性肝病（ALD）的早期表现， 进展为酒精性肝炎和肝硬化，并持续滥用酒精。肝脏脂肪变性是一种可逆的 ALD的早期阶段，因此是治疗干预的主要目标。我们的长远目标是 (i)了解酒精性脂肪变性发展的机制;（ii）制定策略， 治疗/预防这种和其他具有相似组织病理学和进展史的脂肪肝疾病。 我们以前已经表明，减少磷脂酰乙醇胺甲基转移酶（PEMT）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），这是必需的 正常VLDL组装和分泌。我们进一步表明，用甜菜碱（一种甲基供体）处理， 使PEMT催化的PC合成正常化，以促进VLDL分泌并预防酒精性脂肪变性。 肝细胞质脂滴（LDs）在VLDL形成中起重要作用 生物起源这是因为极低密度脂蛋白的组装是由储存在这些低密度脂蛋白中的甘油三酯的可用性来调节的 其必须被水解以提供用于VLDL组装的底物。LD被单层的 磷脂; PC是最丰富的类别，其次是PE和其他。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，即受损的磷脂甲基化 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- 在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 产生扩大的LD，LD相关蛋白的补体发生显著改变。这些 这些变化共同影响LD甘油三酯储存的脂解，破坏了 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 酒精性脂肪变性通过使LD PC：PE比率和VLDL生物合成正常化。 为了验证我们的假设，我们提出以下具体目标： 具体目的1：表征乙醇如何改变肝脏LD的磷脂和蛋白质组成。 具体目的2：检查酒精对LD脂解的影响，以动员甘油三酯储存， VLDL分泌。 具体目标3：确定甜菜碱对酒精诱导的LD动力学改变的影响。 这些研究的完成将使我们深入了解维持必需甲基化的重要性。 PEMT催化的反应在调节脂滴动力学和阻止 酒精性脂肪变性和其他慢性肝病，包括非酒精性肝病。

项目成果

Lipidomic Analysis of Liver Lipid Droplets after Chronic Alcohol Consumption with and without Betaine Supplementation.

• DOI: 10.3390/biology12030462
• 发表时间: 2023-03-16
• 期刊: Biology
• 影响因子: 4.2

Ghrelin regulates adipose tissue metabolism: Role in hepatic steatosis.

• DOI: 10.1016/j.cbi.2020.109059
• 发表时间: 2020-05-01
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Rasineni K;Kubik JL;Knight KL;Hall L;Casey CA;Kharbanda KK
• 通讯作者: Kharbanda KK

The Loss of α- and β-Tubulin Proteins Are a Pathological Hallmark of Chronic Alcohol Consumption and Natural Brain Ageing.

α-和β-微管蛋白蛋白的丧失是长期饮酒和自然脑衰老的病理标志。

• DOI: 10.3390/brainsci8090175
• 发表时间: 2018-09-11
• 期刊: Brain sciences
• 影响因子: 3.3
• 作者: Labisso WL;Raulin AC;Nwidu LL;Kocon A;Wayne D;Erdozain AM;Morentin B;Schwendener D;Allen G;Enticott J;Gerdes HK;Johnson L;Grzeskowiak J;Drizou F;Tarbox R;Osna NA;Kharbanda KK;Callado LF;Carter WG
• 通讯作者: Carter WG

Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells.

• DOI: 10.3390/biom11101497
• 发表时间: 2021-10-11
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: New-Aaron M;Thomes PG;Ganesan M;Dagur RS;Donohue TM Jr;Kusum KK;Poluektova LY;Osna NA
• 通讯作者: Osna NA

Acute ethanol-induced liver injury is prevented by betaine administration.

• DOI: 10.3389/fphys.2022.940148
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4