PPAR delta functions in liver

PPAR δ 在肝脏中的功能

• 批准号: 8069577
• 负责人: Chih-Hao Lee
• 金额: $ 29.07万
• 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 2012-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069577
• 关键词: Acyltransferase; Albumins; Biological Assay; Cells; Collaborations; Data; Diet; Exhibits; Family; Fatty Acids; Fatty-acid synthase; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; Homeostasis; Hyperglycemia; Insulin Resistance; Knock-out; Knockout Mice; Lipids; Lipoproteins; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Muscle; Obesity; PPAR delta; Pathway interactions; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phenotype; Physiological; Play; Process; Production; Research Personnel; Role; Site; Testing; Tissues; Tracer; Very low density lipoprotein; adenoviral-mediated; blood glucose regulation; carbohydrate metabolism; complement C3f; db/db mouse; design; fasting glucose; fatty acid metabolism; fatty acid oxidation; feeding; glucose metabolism; glucose production; improved; in vivo; insulin sensitivity; lipid metabolism; member; metabolic abnormality assessment; mouse model; novel; novel therapeutics; oxidation; prevent; programs; prospective; receptor; research study; small hairpin RNA; stable cell line; therapeutic target; tool; vector control

DESCRIPTION (provided by applicant): Members of the peroxisome proliferator-activated receptors (PPARs) regulate important transcriptional programs to maintain metabolic homeostasis and as such are current and prospective therapeutic targets to treat metabolic diseases. Our long-term goal is to understand the regulatory mechanisms in each of the metabolically active tissues through which PPAR? (also referred to as PPAR?) controls metabolism. Previous studies have suggested that this receptor increases fatty acid ?-oxidation in peripheral tissues to prevent diet-induced obesity. Using mouse models of insulin resistance, our results have identified the liver as an additional site of PPAR? action in regulating glucose and fatty acid metabolism as well as insulin sensitivity. In contrast to its activity in the periphery, we found that PPAR? activation lowers glucose levels through regulation of glucose utilization pathways, including glycogen and fatty acid synthesis. The hypothesis behind this proposal is that PPARd plays an important role in controlling hepatic lipid and carbohydrate metabolism through a three-step energy substrate switching mechanism, in which it promotes glucose utilization in liver for the synthesis of glycogen and fatty acids. The newly made lipids are subsequently delivered by VLDL and utilized in the periphery. The specific aims are designed to determine the molecular mechanisms by which PPAR? regulates these processes, which should identify novel therapeutic pathways to control the progression of metabolic diseases, such as insulin resistance.

描述（由申请人提供）：过氧化物酶体增殖物激活受体（PPAR）的成员调节重要的转录程序以维持代谢稳态，因此是治疗代谢疾病的当前和未来的治疗靶标。我们的长期目标是了解每个代谢活跃组织中 PPAR 的调节机制？ （也称为 PPAR？）控制新陈代谢。先前的研究表明，该受体可增加外周组织中的脂肪酸β-氧化，以预防饮食引起的肥胖。使用胰岛素抵抗小鼠模型，我们的结果已确定肝脏是 PPAR 的另一个部位？调节葡萄糖和脂肪酸代谢以及胰岛素敏感性的作用。与其在外周的活动相反，我们发现PPAR？激活通过调节葡萄糖利用途径（包括糖原和脂肪酸合成）来降低葡萄糖水平。该提议背后的假设是，PPARd 通过三步能量底物转换机制在控制肝脏脂质和碳水化合物代谢中发挥重要作用，其中它促进肝脏中葡萄糖的利用以合成糖原和脂肪酸。新制造的脂质随后由 VLDL 输送并在外周利用。具体目标是确定 PPAR 的分子机制？调节这些过程，这应该确定新的治疗途径来控制代谢疾病（例如胰岛素抵抗）的进展。