The Molecular Regulation of Lipoprotein Lipase Activity

脂蛋白脂肪酶活性的分子调控

• 批准号: 10020172
• 负责人: Benjamin S Roberts
• 金额: $ 2.27万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020172
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adipocytes; Adipose tissue; Affect; Affinity; Autophagocytosis; Binding; Blood; Cardiovascular Diseases; Cell Fractionation; Cell membrane; Cells; Cues; Cultured Cells; Disease; Enzymes; Event; Fluorescence Microscopy; Fractionation; Genes; Genetic Transcription; Glucose; Glucose Transporter; Golgi Apparatus; Guanosine Triphosphate Phosphohydrolases; Heart Diseases; Insulin; Insulin Resistance; Lipoproteins; Lysosomes; Mass Spectrum Analysis; Measures; Metabolic; Microscopy; Molecular; Monitor; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Physiological; Play; Post-Translational Protein Processing; Protein Analysis; Proteins; Proteomics; Regulation; Reporting; Risk; Risk Factors; Role; Route; Secretory Vesicles; Serum; Signal Transduction; Sorting - Cell Movement; Tankyrase; Testing; Tissues; Transcriptional Regulation; Triglycerides; Vesicle; Western Blotting; crosslink; experience; experimental study; feeding; heparin proteoglycan; imaging study; inhibitor/antagonist; insulin signaling; knock-down; lipoprotein lipase; live cell microscopy; mortality; novel; particle; rab GTP-Binding Proteins; response; syndecan; trafficking; vesicular release

Abstract Heart disease is the leading cause of mortality worldwide. One significant risk factor for developing heart disease is uncontrolled high circulating triglycerides. The enzyme Lipoprotein Lipase (LPL) hydrolyzes triglycerides packaged in circulating lipoprotein particles. For this reason, LPL activity and levels are closely correlated with the risk of developing cardiovascular disease. Understanding LPL regulation is important for understanding the role of LPL in disease. The transcriptional regulation of the LPL gene has been well characterized. LPL is synthesized in the parenchyma of tissues including adipose and muscle and its transcription is tightly regulated. Post-translationally, LPL is thought to be stored in secretory vesicles and released by unidentified physiological cues. LPL from intracellular stores is actively degraded in lysosomes. It is not clear how this LPL is targeted for degradation as opposed to secretion. One clue to this regulation comes from Type 2 Diabetes (T2D). Insulin signaling is essential for normal LPL activity and patients with insulin resistance experience reduced LPL activity. We hypothesize that insulin influences LPL stability to regulate its trafficking. The objective of this proposal is to understand the molecular mechanisms of LPL trafficking in adipocytes. In aim 1, we will examine the intracellular trafficking and degradation of LPL in adipose tissue. In aim 2 we will describe the role of Tankyrase 1 in LPL trafficking. We will accomplish these aims using Western blotting, fixed-cell, cell fractionation and live-cell microscopy. These studies extend the fundamental molecular mechanisms of LPL regulation and identify new targets for treating LPL deficiency during T2D.

抽象的 心脏病是全世界死亡的主要原因。患心脏病的一项重要危险因素 是不受控制的高循环甘油三酯。脂蛋白脂肪酶 (LPL) 水解甘油三酯 包装在循环脂蛋白颗粒中。因此，LPL 活性和水平与 患心血管疾病的风险。了解 LPL 监管对于理解 LPL 在疾病中的作用。 LPL 基因的转录调控已得到很好的表征。 LPL是 在包括脂肪和肌肉在内的组织实质中合成，其转录受到严格调控。 翻译后，LPL 被认为储存在分泌囊泡中，并由不明的生理学释放。 提示。来自细胞内储存的 LPL 在溶酶体中被积极降解。目前还不清楚LPL的目标是如何 降解而不是分泌。这一规定的一条线索来自 2 型糖尿病 (T2D)。胰岛素 信号传导对于正常的 LPL 活性至关重要，而胰岛素抵抗患者的 LPL 活性降低。 我们假设胰岛素影响 LPL 稳定性以调节其运输。该提案的目的是 了解脂肪细胞中 LPL 运输的分子机制。在目标 1 中，我们将检查细胞内 LPL 在脂肪组织中的运输和降解。在目标 2 中，我们将描述端锚聚合酶 1 在 LPL 中的作用 贩运。我们将使用蛋白质印迹、固定细胞、细胞分级分离和活细胞来实现这些目标 显微镜。这些研究扩展了 LPL 调节的基本分子机制并确定了新的 治疗 T2D 期间 LPL 缺乏的目标。