Role of PAT proteins in ectopic fat deposition

异位脂肪沉积，即脂肪组织外的脂滴聚集，是很好的。 被认为是胰岛素抵抗和“代谢综合征”发展的强有力的预后因素 在肥胖症和脂肪营养不良患者中。因此，一个关键的问题被提出了，即异位 脂肪不仅仅是疾病的标志，实际上也是疾病的媒介。我们现在在一个肝细胞上有了初步结果 脂滴表面蛋白siRNA基因抑制物诱导胰岛素抵抗的培养体系， 提供了一些最初的证据，表明异位脂肪确实是疾病的媒介。要继续，请继续 这是一条更好地理解异位脂肪相关病理生理学的有希望的研究路线 沉积，我们建议研究脂滴表面蛋白的功能和机制来控制 非成脂细胞和组织的脂解作用以及脂滴组成和潜在的变化 活动是肥胖的这些病理生理后果的根本原因，而且可能是 治疗干预的新生化途径。 在健康状态下，脂滴通过以下方式维持细胞非酯脂肪酸(NEFA)的动态平衡 将任何多余的NEFA储存为甘油三酯(TAG)，并在需要时释放它。这种最小化的能力 过量的NEFA被认为可以防止“脂毒性”，其特征是导致胰岛素抵抗。 炎症，在极端情况下细胞凋亡。此外，存储和存储的两条路径 NEFA的释放涉及二酰基甘油酯(DAG)的中间产物，DAG也有一个信号转导 功能。通过不受调节的脂解作用而增加DAG的产生可能在 与异位脂肪相关的不良反应。因此，调节脂滴的储存和释放 NEFA是异位脂肪致病机制的有力候选者。虽然脂类 液滴的调节仍然知之甚少，许多研究表明，一个或多个成员 PAT蛋白家族似乎总是与脂滴表面有关，其中一种，Perilipin， 已被证明有助于调节脂肪细胞的脂肪分解。PAT蛋白家族由脂滴外壳组成 蛋白质具有很高的初级序列，与载脂蛋白相似，有些是组织特有的。 因此，这项建议的总体目标是了解三种疾病的病理生理学重要性 已知表达的功能未鉴定的PAT蛋白、ADRP、TIP47和PAT-1(或MLDP) 非成脂组织。根据我们的初步结果，这些蛋白质是调节的有力候选者。 非成脂组织中的脂滴脂解及其功能障碍可能是异位脂肪介导的原因 胰岛素抵抗。这些拟议的研究将检验这一假设，如果正确，将提供一种方法 疾病的预防或治疗干预。

Ectopic fat deposition, which is the accumulation of lipid droplets outside the adipose tissue, is well recognized as a strong prognostic factor for the development of insulin resistance and "metabolic syndrome" in obesity and people with lipodystrophies. Therefore a key question has been raised as to whether ectopic fat is not simply a marker but in fact a mediator of disease. We now have preliminary results in a liver cell culture system where siRNA gene inhibitors of lipid droplet surface proteins induce insulin resistance, providing some of the first evidence suggesting that ectopic fat is indeed a mediator of disease. To continue this promising line of investigation to better understand the pathophysiology associated with ectopic fat deposition, we propose to investigate the function and mechanism of lipid droplet surface protein to control lipolysis in non-adipogenic cells and tissues as well as potential changes in lipid droplet composition and activity as the underlying cause of these pathophysiological consequences of obesity, and potentially as a new biochemical pathway for therapeutic intervention. In the healthy state, lipid droplets maintain cellular non-esterifedfatty acid (NEFA) homeostasis by storing any excess NEFA as triglyceride (TAG) and releasing it when needed. This ability to minimize excess NEFA is thought to provide protection from "lipotoxicity", characterized by insulin resistance leading to inflammation, and in extreme cases cellular apoptosis. In addition, both of the pathways for storage and release of NEFA involve the intermediate production of diacylglyceride (DAG), which also has a signaling function. It is possible that an increase in DAG production by disregulated lipolysis may have a role in the adverse effects associated with ectopic fat. Therefore, regulation of lipid droplet storage AND release of NEFA is a strong candidate for a mechanism by which ectopic fat contributes to disease. Although lipid droplet regulation remains poorly understood, numerous studies have revealed that one or more membersof the PAT protein family always seem to be associated with the lipid droplet surface and one, Perilipin, has been shown to help regulate adipocyte lipolysis. The PAT protein family is composed of lipid droplet coat proteins sharing high primary sequences, and similarity with apolipoproteins, and some are tissue specific. Therefore, the overall goal of this proposal is to understand the pathophysiological importance of three functionally uncharacterized PAT proteins, ADRP,TIP47 and PAT-1 (or MLDP) known to be expressedin non-adipogenic tissues. Given our preliminary results, these proteins are strong candidates for regulating lipid droplet lipolysis in non-adipogenic tissues and their disfunction is a likely cause of ectopic fat mediated insulin resistance. These proposed studies will test this hypothesis, and if correct provide an approach for prevention of disease or therapeutic intervention.