Lipotoxicity in Alcoholic Liver Disease

酒精性肝病的脂毒性

• 批准号: 10447199
• 负责人: ZHANXIANG ZHOU
• 金额: $ 41.11万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447199
• 关键词: ASCL1 gene; Acetaldehyde; Acyl Coenzyme A; Adipocytes; Alcoholic Liver Diseases; Alcohols; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Aryl Hydrocarbon Receptor; Biochemical Reaction; Cell Death; Cells; Cirrhosis; Coenzyme A; Coenzyme A Ligases; Data; Defect; Deposition; Development; Diet therapy; Dietary Intervention; Disease; Eicosanoids; Evaluation; Exhibits; Experimental Models; FDA approved; Fatty Acids; Functional disorder; Funding; Generations; Genetic Transcription; Goals; Gold; Grant; Hepatic; Hepatitis; Hepatocyte; Homeostasis; Impairment; In Vitro; Inflammation Mediators; Intervention; Knock-out; Knowledge; Lecithin; Ligands; Link; Lipids; Liver; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Production; Protein Isoforms; Reporting; Research; Role; Severity of illness; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Triglycerides; United States; Very low density lipoprotein; alcohol exposure; alcohol response; aryl hydrocarbon receptor ligand; diacylglycerol O-acyltransferase; dietary; effective therapy; endoplasmic reticulum stress; in vivo; lipid mediator; lipine; liver injury; molecular targeted therapies; mortality; mouse model; novel; overexpression; oxidation; peroxisome; preservation; prevent; problem drinker; receptor expression; therapeutic development

PROJECT SUMMARY / ABSTRACT Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality in the United States and worldwide. Unfortunately, there is currently no FDA approved medication for any stage of ALD. Advancing our knowledge on the pathophysiologic mechanisms of ALD will certainly pave the way to development of therapeutic interventions. One of the known mechanisms of alcohol-induced liver injury is the perturbation of lipid metabolic pathways. In fact, alcoholic steatosis is the earliest pathological change in ALD. In the past funding period, we have shown that instead of triglyceride, accumulated free fatty acid (FFA) levels positively correct with disease severity in experimental models of ALD. However, how alcohol causes FFA accumulation in the liver and the feasibility of FFA lowering approaches for treating ALD are still open questions to be elucidated. Through profiling hepatic FFAs, we found that the most significantly altered and abundant FFA species were long chain FAs (LCFA) which were increased by alcohol. On the other hand, their activated forms, long chain acyl-CoAs, were decreased by alcohol, suggesting a defect in FA activation by long chain acyl-CoA synthetase (ACSL). Our preliminary study detected two ACSL isoforms in the liver, ACSL1 and ACSL4, that both were downregulated after alcohol exposure. ACSL1 is a major form of hepatic ACSLs that is critical for channeling FA to mitochondrial β-oxidation, whereas ACSL4 specifically targets arachidonic acid (AA) metabolism and has been reported to be critically involved in ER VLDL lipidation. Along with reduced VLDL secretion rate as well as its lipidation status, we indeed found that alcohol exposure decreases hepatic AA-CoA despite an increased AA. Moreover, we found that the expression of ACSL1 and ACSL4 were positively correlated with aryl hydrocarbon receptor both in vivo and in vitro. All evidence collected strongly supports a novel concept that defect in ACSL-mediated hepatic FA channeling plays a critical role in FA disposal disorder and in alcohol-induced lipotoxicity, which is tightly controlled by AhR. We will test the hypothesis in 3 aims. In Aim 1, we will investigate the role of ACSL1 in directing the metabolic switch toward mitochondrial β-oxidation versus ER ω-oxidation in order to reduce toxic lipid production from ER and to prevent lipotoxicity in ALD. In Aim 2, we will explore how ACSL4 is involved in AA channeling to ER for VLDL lipidation and/or to peroxisome for β-oxidation other than converting to toxic lipid mediators. In Aim 3, we will determine whether the expression of ACSL is regulated by AhR at transcription level. We also will test the effect of endogenous AhR ligand in reversing ACSL expression and protecting alcohol- induced lipotoxicity. Understanding these mechanisms will enable us to develop targeted dietary therapies to prevent and treat ALD.

项目摘要 /摘要 酒精性肝病（ALD）是美国和全球发病率和死亡率的主要原因。 不幸的是，目前尚无FDA批准的ALD阶段的药物。促进我们的知识 ALD的病理生理机制肯定会为治疗的发展铺平道路 干预措施。酒精引起的肝损伤的已知机制之一是脂质代谢的扰动 途径。实际上，酒精脂肪变性是ALD中最早的病理变化。在过去的资金期间，我们 已经表明，累积的游离脂肪酸（FFA）水平与疾病正相同，而不是甘油三酸酯，而不是甘油三酸酯 ALD实验模型中的严重程度。但是，酒精如何导致FFA在肝脏和 FFA降低方法治疗ALD的可行性仍然是旨在阐明的问题。通过分析 Hepati FFA，我们发现最显着变化和丰富的FFA物种是长链FAS （LCFA）通过酒精增加。另一方面，它们的活化形式是长链酰基辅助，是 通过酒精减少，表明长链酰基辅酶A合成酶（ACSL）的FA激活缺陷。我们的 初步研究检测到肝脏ACSL1和ACSL4中的两个ACSL同工型，它们都下调了 ACSL1是肝ACSL的一种主要形式，对于将FA引导至线粒体至关重要 β-氧化，而ACSL4特异性靶向花生四烯酸（AA）代谢，据报道为 与ER VLDL脂质相关。以及降低的VLDL分泌率及其脂质状态， 我们确实发现酒精暴露会降低肝AA-COA渴望增加的AA。而且，我们发现 ACSL1和ACSL4的表达与芳基烃受体呈正相关 并在体外。所有收集的证据都强烈支持一个新颖的概念，该概念在ACSL介导的肝FA中缺陷 引导在FA处置障碍和酒精引起的脂肪毒性中起着至关重要的作用，这是紧密的 由AHR控制。我们将在3个目标中检验该假设。在AIM 1中，我们将研究ACSL1在 将代谢转换指向线粒体β-氧化与ERω氧化，以减少有毒 脂质从ER产生并防止ALD中的脂肪毒性。在AIM 2中，我们将探讨ACSL4如何参与 除了转化为有毒脂质之外 调解人。在AIM 3中，我们将确定ACSL的表达是否在转录水平下由AHR调节。 我们还将测试内源性AHR配体在逆转ACSL表达和保护酒精的影响 诱导的脂肪毒性。了解这些机制将使我们能够开发针对性的饮食疗法 预防和治疗ALD。