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

鱼油衍生呋喃对肝脂肪变性和肥胖的主要保护作用

基本信息

批准号：
9904142
负责人：
Francisco Jose Schopfer
金额：
$ 39.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904142
关键词：
Acetyl-CoA Carboxylase Acids Acute Adult Affect Analytical Chemistry Animal Model Animals Binding Biochemical Biochemistry Biological Assay Biological Models Clinical Clinical Chemistry Clinical Data Clinical Pharmacology Clinical Research Coenzyme A Consequentialism Data Data Analyses Deposition Development Diabetes Mellitus Diet Dietary Component Dose Drug Kinetics Drug Prescriptions Energy Intake Energy Metabolism Enzymatic Biochemistry Enzymes Epidemiology FDA approved Fatty Acids Fatty Liver Fatty acid glycerol esters Fish Oils Formulation Furans Genetic Genetic Models Glucuronides Glycolysis Half-Life Hepatic Hepatocyte High Fat Diet High Pressure Liquid Chromatography Human Hypertriglyceridemia Insulin Resistance Intake Knowledge Lead Life Expectancy Lipids Lipolysis Liver Mass Spectrum Analysis Metabolic Metabolic Pathway Metabolic syndrome Minor Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oils Omega-3 Fatty Acids Organic Synthesis Pharmacology Plasma Play Proteins Proteomics Rattus Regulation Reporting Research Rodent Role Serum Signal Transduction Solid Supplementation Synthesis Chemistry Techniques Testing Therapeutic Toxicology Triglycerides Urine Weight Gain Woman base comorbidity fatty acid oxidation global health glucose tolerance healthy volunteer human model in vivo inhibitor/antagonist lipid biosynthesis lipid metabolism men metabolomics multidisciplinary non-alcoholic fatty liver disease novel pre-clinical prevent protective effect response stem tool volunteer

项目摘要

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.

项目摘要肥胖症是日益增长的全球健康燃烧，将几种合并症与包括非 - 酒精脂肪肝病，高甘油三酸酯，胰岛素抵抗和2型糖尿病（T2D），降低寿命期望和质量。鱼油是重要的饮食成分，可提供必需的omega-3脂肪酸（ω-3 fa），并且有效减少了严重的高甘油三酯血症。更好地了解鱼油代谢产物和它们的作用，一种代谢组学对健康志愿者的尿液和血清lovaza的方法进行了FDA级批准的Omega-3公式。 Furan CMPF是主要代谢物，其次是其他几个Furans及其麸质。为了评估其影响，喂养高脂饮食的小鼠是管理CMPF，以达到与在洛瓦萨治疗的人类中观察到的水平相同的水平。 CMPF 减少血浆和肝甘油三酸酯并减少肝脂肪变性，概括了报道的两者动物和人类的洛夫萨和鱼油处理。在鱼油和洛夫萨（Lovaza）。此外，我们发现呋喃脂肪酸结合并抑制肝乙酰辅酶A 羧化酶提供了一种作用机理。基于这些高度挑衅的初步结果目前，我们假设鱼油呋喃是负责的重要生物活性化合物鱼油引起的肝脂质代谢的变化是通过代谢途径的急性调节特别的，抑制乙酰辅酶A羧化酶。该假设将通过追求以下内容进行检验具体目标 AIM 1：定义Lovaza和Fo，剂量，暴露和药代动力学的FUFA水平。目标2：确定FUFA在依赖Lovaza的TG减少和NAFLD保护方面的作用。 AIM 3：定义肝蛋白靶标，代谢作用以及ACC对FUFA受保护作用的作用。基于质谱的策略的发展，以识别和表征呋喃，应用热移评估以确定结合伴侣，合成策略，脂肪组研究和代谢组学评估支持一种坚实的方法，以确定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的大鼠模型中进行测试，并在 ω-3 fa。该提案的成功完成将定义弗兰斯在针对鱼油描述的有益效果。这些是鱼油中存在的潜在饮食ACC抑制剂药理学相关的浓度，是具有安全毒理学特征的合格杂质。该建议旨在填补ω-3 FA治疗中知识的关键空白，并有可能重新进行定义与补充ω-3 FA对脂肪生成，脂解和脂解和的影响有关的电流范例糖酵解。