The Molecular Regulation of Lipoprotein Lipase Activity

摘要 心脏病是世界范围内死亡的主要原因。患心脏病的一个重要危险因素 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 包装在循环的脂蛋白颗粒中。因此，LPL活性和水平与以下因素密切相关： 患心血管疾病的风险。了解LPL法规对于了解 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 在包括脂肪和肌肉的组织的实质中合成，并且其转录受到严格调控。 研究后，LPL被认为储存在分泌囊泡中，并通过未鉴定的生理途径释放。 线索来自细胞内储存的LPL在溶酶体中被主动降解。目前尚不清楚这种LPL是如何针对 降解而不是分泌。这种调节的一个线索来自2型糖尿病（T2D）。胰岛素 信号传导对于正常的LPL活性是必需的，并且具有胰岛素抗性的患者经历降低的LPL活性。 我们假设胰岛素影响LPL的稳定性以调节其运输。这项建议的目的是 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。在目的2中，我们将描述端锚聚合酶1在LPL中的作用。 贩卖人口我们将使用Western印迹、固定细胞、细胞分级分离和活细胞 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。

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.