Role of PAT proteins in ectopic fat deposition

异位脂肪沉积，即脂肪组织外脂滴的积聚，是很好的 被认为是胰岛素抵抗和“代谢综合征”发展的一个强有力的预后因素 肥胖症和脂肪代谢障碍的人。因此，一个关键问题已经提出，是否异位 脂肪不仅仅是一个标志，事实上还是疾病的媒介。我们现在有了一个肝细胞的初步结果 其中脂滴表面蛋白的siRNA基因抑制剂诱导胰岛素抗性的培养系统， 提供了一些初步证据，表明异位脂肪确实是疾病的媒介。继续 这一有希望的研究路线，以更好地了解与异位脂肪相关的病理生理 沉积，我们建议研究脂滴表面蛋白的功能和机制， 非脂肪形成细胞和组织中的脂解以及脂滴组成的潜在变化， 活动作为肥胖症的这些病理生理后果的根本原因，并可能作为一种 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脂肪酸（NEFA）稳态： 将任何过量的NEFA储存为甘油三酯（TAG），并在需要时释放。这种能力可以最小化 过量的NEFA被认为提供了对“脂毒性”的保护，“脂毒性”的特征在于导致胰岛素抵抗的胰岛素抵抗。 炎症，在极端情况下细胞凋亡。此外，这两种储存途径和 NEFA的释放涉及二酰基甘油酯（DAG）的中间产物，其也具有信号传导作用。 功能可能由于不受调节的脂解作用而增加DAG的产生可能在这一过程中起作用。 与异位脂肪相关的副作用。因此，调节脂滴的储存和释放， NEFA是异位脂肪促成疾病的机制的有力候选者。虽然脂质 液滴调节仍然知之甚少，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相关，其中之一Perilipin 被证明有助于调节脂肪细胞的脂解。PAT蛋白家族由脂滴外壳组成， 蛋白质共享高的一级序列，与载脂蛋白相似，有些是组织特异性的。 因此，本提案的总体目标是了解三种疾病的病理生理学重要性， 已知表达在大肠杆菌中的功能上未表征的PAT蛋白、ADRP、TIP 47和PAT-1（或MLDP）， 非脂肪形成组织。鉴于我们的初步结果，这些蛋白质是调节 非脂肪形成组织中的脂滴脂解及其功能障碍可能是异位脂肪介导的 胰岛素抵抗这些拟议中的研究将检验这一假设，如果正确的话，将提供一种方法， 预防疾病或治疗干预。

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.