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

项目摘要 肥胖是一个日益严重的全球健康负担，它与包括非肥胖在内的几种共病密切相关 酒精性脂肪性肝病、高甘油三酯血症、胰岛素抵抗和2型糖尿病(T2D)，减少生命 期望和质量。鱼油是一种重要的饮食成分，可提供必需的omega-3脂肪酸 (Ω-3 FA)，并能有效降低严重的高甘油三酯血症。为了更好地了解鱼油代谢物和 用代谢组学方法研究服用洛伐他汀对健康志愿者尿液和血清的影响 FDA批准的等级omega-3配方。呋喃CMPF是主要的代谢物， 紧随其后的是其他几种呋喃及其葡萄糖醛酸苷。为了评估其效果，喂食高脂饮食的小鼠 给予CMPF以达到与使用Lovaza治疗的人类观察到的水平相同的水平。CMPF 降低血浆和肝脏甘油三酯，减轻肝脏脂肪变性，概括了在 在动物和人类中使用Lovaza和鱼油治疗。呋喃脂肪酸的存在被证实在 包括鱼油和洛瓦扎。此外，我们还发现呋喃脂肪酸可以结合和抑制肝乙酰辅酶A。 羧基酶，提供一种作用机制。基于这些极具挑衅性的初步结果和 目前的理解是，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诱导肝脏脂质代谢的变化 尤其是对乙酰辅酶A羧基酶的抑制。这一假设将通过追求以下几点来检验 具体目标 目的1：确定氟甲胺在洛伐他滨和FO中的浓度、剂量、暴露和药代动力学。 目的2：确定福发对洛伐他定依赖的甘油三酯的降低和对非酒精性脂肪肝的保护作用。 目的3：明确肝脏蛋白质靶点、代谢效应以及ACC对FUFA的保护作用。 基于质谱学的策略的发展，以识别和表征呋喃，应用 用于确定结合伙伴、合成策略、脂组研究和代谢组的热位移分析 评估支持确定确定鱼油衍生生物活性呋喃并确定其特征的可靠方法。 合成呋喃脂肪酸将在饮食诱导肥胖的大鼠模型中进行测试，并在 Ω-3 FA.这项提案的成功完成将明确呋喃在 描述了鱼油的有益效果。这些都是有效的饮食ACC抑制剂，存在于鱼油中 药理上相关的浓缩物，是具有安全毒理学特征的合格杂质。 这项建议旨在填补Ω-3FA疗法知识的关键空白，并有可能重新 明确补充Ω-3FA对脂肪生成、脂肪分解和 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.