Predominant protective role in hepatic steatosis and obesity by fish oil-derived furans

项目摘要 肥胖是一种日益严重的全球健康负担，与多种合并症密切相关，包括非肥胖症。 酒精性脂肪肝、高脂血症、胰岛素抵抗和2型糖尿病（T2 D），缩短寿命 期望和质量。鱼油是一种重要的膳食成分，提供必需的欧米茄-3脂肪酸 （α-3 FA），并有效降低严重的高血脂症。为了更好地了解鱼油代谢物， 他们的影响，代谢组学方法对健康志愿者的尿液和血清服用Lovaza，临床 级FDA批准的omega-3制剂。呋喃CMPF为主要代谢产物， 然后是几种其它呋喃和它们的葡糖苷酸。为了评估其效果，喂食高脂肪饮食的小鼠被 给予CMPF以达到与在用Lovaza治疗的人中观察到的水平相当的水平。CMPF 降低血浆和肝脏甘油三酯，减少肝脏脂肪变性，概括了 动物和人类的Lovaza和鱼油治疗。呋喃脂肪酸的存在被证实， 鱼油和洛伐扎此外，我们发现呋喃脂肪酸结合并抑制肝乙酰辅酶A， 羧化酶，提供作用机制。基于这些极具挑衅性的初步结果， 根据目前的了解，我们假设鱼油呋喃是重要的生物活性化合物，负责 鱼油通过急性调节代谢途径引起的肝脏脂质代谢变化， 特别是抑制乙酰辅酶A羧化酶。这一假设将通过以下方式进行检验： 具体目标 目的1：确定Lovaza和FO中的FuFA水平、剂量、暴露量和药代动力学。 目的2：确定FuFA在Lovaza依赖性TG降低和NAFLD保护中的作用。 目的3：确定肝脏蛋白靶点，代谢效应和ACC对FuFA保护作用的作用。 基于质谱的呋喃识别和表征策略的发展， 确定结合配偶体的热转移试验、合成策略、脂质组学研究和代谢组学研究 评估支持一种可靠的方法来明确识别和表征鱼油衍生的生物活性呋喃。 合成呋喃脂肪酸将在饮食诱导的肥胖症大鼠模型中进行测试，并在以下背景下进行评估： -3 FA。该提案的成功完成将确定呋喃在这一领域的参与和作用。 对鱼油的有益效果。这些都是有效的饮食ACC抑制剂存在于鱼油中， 具有药理学相关浓度，是具有安全毒理学特征的合格杂质。 该提案旨在填补α-3 FA治疗知识的关键空白，并可能重新 定义与补充β-3 FA对脂肪生成、脂解和 糖酵解

Project Summary Obesity is a growing global health burden that strongly associates with several comorbidities including non- alcoholic fatty liver disease, hypertriglyceridemia, insulin resistance, and type 2 diabetes (T2D), reducing life expectancy and quality. Fish oil is an important dietary component that provides essential omega-3 fatty acids (Ω-3 FA) and is effective reducing severe hypertriglyceridemia. To better understand fish oil metabolites and their effects, a metabolomics approach on urine and serum of healthy volunteers taking Lovaza, a clinical grade FDA-approved omega-3 formulation, was performed. The furan CMPF was the major metabolite, followed by several other furans and their glucuronides. To evaluate its effects, mice fed a high-fat diet were administered CMPF to achieve levels equivalent to the ones observed in humans treated with Lovaza. CMPF lowered plasma and liver triglycerides and reduced hepatic steatosis, recapitulating the effects reported both in animals and in humans for Lovaza and fish oil treatments. The presence of furan fatty acids was confirmed in both fish oil and Lovaza. Moreover, we found furan fatty acid to bind and inhibit hepatic acetyl-CoA carboxylase, providing a mechanism of action. Based on these highly provocative preliminary results and current understanding, we hypothesize that fish oil furans are significant bioactive compounds responsible for fish oil-induced changes in hepatic lipid metabolism through acute modulation of metabolic pathways, in particular, inhibition of acetyl-CoA carboxylase. This hypothesis will be tested by pursuing the following Specific Aims Aim 1: Define FuFA levels in Lovaza and FO, dose, exposure and pharmacokinetics. Aim 2: Establish the role of FuFA on Lovaza-dependent TG reduction and NAFLD protection. Aim 3: Define hepatic protein targets, metabolic effects and role of ACC on FuFA protective effects. The development of mass spectrometry-based strategies to identify and characterize furans, application of thermal shift assay to determine binding partners, synthetic strategies, lipidomic studies and metabolomic assessments support a solid approach to definitively identify and characterize fish oil-derived bioactive furans. Synthetic furan fatty acids will be tested in a rat model of diet-induced obesity and evaluated in the context of Ω-3 FA. A successful completion of this proposal will have defined the participation and role of furans in the beneficial effects described for fish oil. These are potent dietary ACC inhibitors present in fish oil at pharmacologically relevant concentrations and are qualified impurities with a safe toxicological profile. This proposal is designated to fill critical gaps in knowledge in Ω-3 FA therapeutics and can potentially re- define current paradigms related to the impact of Ω-3 FA supplementation on lipogenesis, lipolysis, and glycolysis.