PPAR Delta Functions in Liver

肝脏中 PPAR Delta 功能

• 批准号: 8728813
• 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
• 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/8728813
• 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

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(申请人提供)：肥胖导致主要新陈代谢组织功能障碍。葡萄糖-脂肪酸循环，也被称为兰德尔假说，为肥胖症中血脂水平升高如何导致糖代谢紊乱和胰岛素抵抗提供了第一个基本概念。脂毒性被认为是由于脂肪细胞的脂质溢出所致。人类的脂质组学研究表明，血清的脂肪成分更接近肝脏，而不是白色脂肪组织。此外，肝脏代谢功能的节律性已知将摄食行为与底物使用的生化反应耦合在一起，这表明肝脏新生脂肪生成在代谢动态平衡中也发挥着重要作用。在之前的资助阶段，我们建议研究核受体PPAR在肝脏新生脂肪形成中的作用。我们发现，PPAR和Fas、ACC1、ACC2和SCD1等致脂基因在小鼠肝脏中的表达受到昼夜节律的调节，在暗(摄食)周期中活跃。在肝脏特异性PPAR基因敲除小鼠(LPPARDKO)中，暗周期中ACC1的上调被取消，而Fas、ACC2和SCD1的昼夜节律模式发生了变化。有趣的是，肝脏脂肪生成程序的昼夜节律与肌肉脂肪酸摄取/利用的每日循环相关，这在LPPARDKO小鼠中是减弱的。利用无偏液相色谱质谱(LC-MS)代谢组学方法，我们鉴定了1-硬脂酰基-2-油酰基-2-甘油-3-磷胆碱(18：0-18：1PC或SOPC)，这是一种与PPAR调节的造脂程序相关的磷脂，其血清浓度在暗周期达到峰值。小鼠注射SOPC可促进肝脏脂肪合成/输出和肌肉FA的利用。在更新方案中，我们将检验PPAR调节的造脂程序部分通过SOPC调节肝脏代谢和肌肉脂肪酸利用的假设。这项研究计划是创新的，因为它描述了一种机制，通过这种机制，生物钟将摄食的代谢过程与外周能量底物的利用保持一致。这也是首批研究之一，这些研究使用无偏见的方法，使用多个代谢性疾病的小鼠遗传模型来检查代谢物。这项研究有望开辟新的研究领域，并具有重要的临床意义，因为这种新的脂质信号可能作为代谢性疾病的标志物和治疗靶点。