PPAR Delta Functions in Liver

肝脏中 PPAR Delta 功能

基本信息

批准号：
8921962
负责人：
Chih-Hao Lee
金额：
$ 35.13万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8921962
关键词：
Adipocytes Adipose tissue Affect Area Attenuated Biochemical Reaction Circadian Rhythms Clinical Fatty Acids Fatty acid glycerol esters Feeding behaviors Functional disorder Funding Gene Expression Genes Genetic Models Glucose Hepatic Homeostasis Human Hypertrophy Injection of therapeutic agent Insulin Resistance Investigation Knock-out Lead Lipids Liver Long-Term Effects Mediating Metabolic Metabolic Diseases Metabolism Modeling Mus Muscle Nonesterified Fatty Acids Nuclear Receptors Obesity Output PPAR delta Pathway interactions Pattern Periodicity Peripheral Peroxisome Proliferator-Activated Receptors Phospholipids Phosphorylcholine Play Regulation Research Role Serum Signal Transduction Testing Tissues Up-Regulation circadian pacemaker cohort fatty acid metabolism feeding gain of function glucose metabolism improved innovation lipid biosynthesis lipid metabolism liquid chromatography mass spectrometry liver metabolism loss of function metabolomics mouse model novel programs response therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Obesity causes dysfunction in major metabolic tissues. The glucose-fatty acid cycle, also known as the Randle hypothesis, provides the first basic concept for how elevated lipid levels in adiposity can cause dysregulated glucose metabolism and insulin resistance. Lipotoxicity is believed to be due to lipid overflow from adipocytes. Lipidomics studies in humans demonstrate that the lipid composition of serum is more closely resembles that of the liver, rather than white adipose tissue. Furthermore, the rhythmicity of hepatic metabolic function is known to couple the feeding behavior to biochemical reactions of substrate usage, suggesting that hepatic de novo lipogenesis also plays an important role in metabolic homeostasis. In the previous funding period, we proposed to examine the function of the nuclear receptor PPAR� in hepatic de novo lipogenesis. We find the expression of PPAR� and lipogenic genes, such as FAS, ACC1, ACC2 and SCD1, in mouse liver is under circadian regulation, being active in the dark (feeding) cycle. In liver-specific PPAR� knockout (LPPARDKO) mice, the up-regulation of ACC1 in the dark cycle is abolished, whereas the circadian pattern of FAS, ACC2 and SCD1 is shifted. Interestingly, the circadian rhythm of the hepatic lipogenic program correlates with the daily cycling of muscle fatty acid uptake/utilization, which is attenuated in LPPARDKO mice. Using unbiased, liquid chromatography-mass spectrometry (LC-MS) metabolomics approaches, we have identified 1-stearoyl-2- oleoyl-sn-glycero-3-phosphocholine (18:0-18:1 PC or SOPC), a phospholipid associated with PPAR�-regulated lipogenic program whose serum concentration peaks in the dark cycle. SOPC injection in mice promotes hepatic lipid synthesis/output and muscle FA utilization. In the renewal proposal, we will test the hypothesis that PPAR�-regulated lipogenic program modulates liver metabolism and muscle fatty acid utilization, in part, though SOPC. This research plan is innovative, as it describes a mechanism through which the circadian clock aligns the metabolic processes of feeding to peripheral energy substrate utilization. It is also on of the first studies, which use unbiased approaches to examine metabolomes using multiple mouse genetic models of metabolic diseases. The study is expected to lead to new areas of research and to have important clinical implication, as this novel lipid signaling may serve as a marker and a therapeutic target of metabolic diseases.

描述（适用提供）：肥胖会导致主要代谢组织功能障碍。葡萄糖脂肪酸周期，也称为randle假设，为脂肪质量升高的脂质水平升高提供了第一个基本概念，如何导致葡萄糖代谢和胰岛素抵抗失调。据信脂毒性是由于脂肪细胞的脂质溢出引起的。人类中的脂质组学研究表明，血清的脂质组成更像肝脏，而不是白色脂肪组织。此外，众所周知，肝代谢功能的节奏性将喂养行为与底物使用的生化反应相结合，这表明肝脂肪生成发生在代谢稳态中也起着重要作用。在上一个资金期间，我们提议检查核受体PPAR的功能。我们发现PPAR的表达。小鼠肝脏中的脂肪生成基因（例如FAS，ACC1，ACC2和SCD1）受昼夜节律调节，在黑暗（进食）周期中活跃。在肝特异性PPAR中，敲除（Lppardko）小鼠，消除了黑暗周期中ACC1的上调，而FAS，ACC2和SCD1的昼夜模式被移动。有趣的是，肝脂肪生成程序的昼夜节律与肌肉脂肪酸摄取/利用率的每日循环相关，后者在lppardko小鼠中减弱。使用无偏的液相色谱 - 质量光谱法（LC-MS）代谢组学方法，我们已经确定了1 stearoyl-2-烯烃-SN-甘油-3-磷酸胆碱（18：0-18：1 PC或SOPC），一种与PPAR调节的脂肪生成程序相关的磷脂，其血清浓度是在黑暗的周期中。小鼠的SOPC注射促进肝脂质合成/输出和肌肉FA利用。在续签建议中，我们将检验以下假设：PPAR调节的脂肪生成程序调节肝脏代谢和肌肉脂肪酸的利用，部分地是SOPC。该研究计划具有创新性，因为它描述了一种机制，昼夜节律时钟通过该机制使喂养的代谢过程与外围能量底物利用率保持一致。它也是在第一批研究中使用的，它使用无偏的方法使用代谢性疾病的多种小鼠遗传模型检查代谢组。这项研究有望导致新的研究领域并具有重要的临床意义，因为这项新型的脂质信号传导可以作为代谢疾病的标志物和治疗靶标。