PPAR Delta Functions in Liver

描述（由申请人提供）：肥胖导致主要代谢组织功能障碍。葡萄糖-脂肪酸循环，也被称为兰德尔假说，为肥胖症中脂质水平升高如何导致葡萄糖代谢失调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。人体脂质组学研究表明，血清的脂质组成更接近肝脏，而不是白色脂肪组织。此外，已知肝脏代谢功能的节律性将摄食行为与底物使用的生化反应偶联，这表明肝脏从头脂肪生成在代谢稳态中也起着重要作用。在上一个资助期，我们建议研究核受体PPAR <$在肝脏新生脂肪生成中的功能。我们发现小鼠肝脏中的过氧化物酶体增殖物激活受体和脂肪生成基因，如FAS、ACC 1、ACC 2和SCD 1的表达受昼夜节律调节，在黑暗（进食）周期中活跃。在肝脏特异性过氧化物酶体增殖物激活受体中，敲除（LPPARDKO）小鼠中，ACC1在暗周期中的上调被消除，而FAS、ACC2和SCD 1的昼夜节律模式被移位。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小鼠中减弱。使用无偏的液相色谱-质谱（LC-MS）代谢组学方法，我们鉴定了1-硬脂酰-2-油酰-sn-甘油-3-磷酸胆碱（18：0 - 18：1 PC或SOPC），这是一种与PPAR调节的脂肪生成程序相关的磷脂，其血清浓度在黑暗周期达到峰值。小鼠SOPC注射促进肝脏脂质合成/输出和肌肉FA利用。在更新提案中，我们将测试这样的假设，即通过SOPC，部分地通过PPAR调节脂肪生成程序调节肝脏代谢和肌肉脂肪酸利用。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，生物钟将进食的代谢过程与外周能量底物利用相结合。这也是第一个研究，使用无偏的方法来检查代谢组，使用多种代谢疾病的小鼠遗传模型。该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。

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.