The Molecular Regulation of Lipoprotein Lipase Activity

摘要 心脏病是世界范围内导致死亡的主要原因。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 包装在循环中的脂蛋白颗粒中。因此，LPL的活性和水平与 患心血管疾病的风险。了解LPL规则对于理解 脂蛋白脂酶在疾病中的作用。LPL基因的转录调控已经被很好地描述了。LPL是 在脂肪和肌肉等组织的实质中合成，其转录受到严格调控。 翻译后，LPL被认为储存在分泌囊泡中，并由不明生理因素释放 暗示。来自细胞内储存的LPL在溶酶体中被积极降解。目前还不清楚这种LPL的目标是什么 降解与分泌相反的降解。这种调节的一个线索来自2型糖尿病(T2D)。胰岛素 信号对正常的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的稳定性，以调节其运输。这项建议的目的是 了解LPL在脂肪细胞中转运的分子机制。在目标1中，我们将检查细胞内 脂联素在脂肪组织中的迁移和降解。在目标2中，我们将描述tankyrase 1在LPL中的作用 贩卖人口。我们将使用Western blotting、固定细胞、细胞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，并发现了新的 T2D治疗LPL缺乏症的目标。

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.