PPAR delta functions in liver

PPAR δ 在肝脏中的功能

• 批准号: 7468380
• 负责人: Chih-Hao Lee
• 金额: $ 29.84万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468380
• 关键词: Acyltransferase; Albumins; Biological Assay; Cells; Collaborations; Data; Diet; Exhibits; Family; Fasting; Fatty Acids; Fatty-acid synthase; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; Homeostasis; Hyperglycemia; Insulin Resistance; Knock-out; 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; Rate; Receptor Activation; Research Personnel; Role; Site; Testing; Tissues; Tracer; Very low density lipoprotein; adenoviral-mediated; blood glucose regulation; carbohydrate metabolism; complement C3f; db/db mouse; design; 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（PPARs）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治疗靶点。我们的长期目标是了解每个代谢活性组织中的调节机制，通过哪些PPAR？(also（简称PPARs）控制新陈代谢。以前的研究表明，这种受体增加脂肪酸？在外周组织中的氧化，以防止饮食诱导的肥胖。使用小鼠模型的胰岛素抵抗，我们的研究结果已确定肝脏作为一个额外的网站的过氧化物酶体增殖物激活受体？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？活化通过调节葡萄糖利用途径（包括糖原和脂肪酸合成）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起重要作用，其中其促进肝脏中葡萄糖的利用以合成糖原和脂肪酸。新产生的脂质随后由VLDL递送并在外周中利用。的具体目标是确定的分子机制，通过何种PPAR？调节这些过程，这应该确定新的治疗途径，以控制代谢疾病的进展，如胰岛素抵抗。