Role of PAT proteins in ectopic fat deposition

PAT 蛋白在异位脂肪沉积中的作用

• 批准号: 8090287
• 负责人: CAROLE A SZTALRYD
• 金额: $ 26.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090287
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Affect; Apolipoproteins; Apoptosis; Behavior; Binding; Biochemical Pathway; Capsid Proteins; Cell Culture System; Cell physiology; Cells; Characteristics; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Deposition; Development; Diet; Disease; Down-Regulation; Family member; Fatty Acids; Fatty acid glycerol esters; Fluorescence Resonance Energy Transfer; Functional disorder; Genes; Genetic; Goals; Hepatocyte; Homeostasis; Hydrolysis; Immunoprecipitation; Inflammation; Inflammatory; Insulin Resistance; Intervention; Investigation; Lead; Lipase; Lipid Binding; Lipids; Lipodystrophy; Lipolysis; Liver; Measurement; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Metabolic; Metabolic syndrome; Methods; Modification; Molecular; Muscle; Muscle Cells; Myocardial tissue; Names; Obese Mice; Obesity; Pathway interactions; Phenotype; Plasmids; Play; Prevention approach; Production; Prognostic Factor; Property; Protein Family; Proteins; Regulation; Research Personnel; Role; Sequence Homology; Serum; Signal Transduction; Small Interfering RNA; Surface; System; Techniques; Testing; Therapeutic Intervention; Tissues; Triad Acrylic Resin; Triglycerides; Work; adverse outcome; cytokine; disorder prevention; fatty acid transport; in vivo; inhibitor/antagonist; insulin signaling; loss of function; member; perilipin; programs; protein function; protein protein interaction; response; therapeutic target; uptake

DESCRIPTION (provided by applicant): 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-esterifed fatty 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 members of 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 expressed in 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.

描述(申请人提供)：异位脂肪沉积，即脂肪组织外积累的脂滴，被公认为肥胖症和脂肪营养不良者发展为胰岛素抵抗和“代谢综合征”的一个强有力的预测因素。因此，提出了一个关键问题，即异位脂肪是否不仅仅是一种标记物，而且实际上是疾病的媒介。我们现在已经在肝细胞培养系统中有了初步的结果，其中脂滴表面蛋白的siRNA基因抑制物诱导胰岛素抵抗，提供了一些第一证据表明异位脂肪确实是疾病的媒介。为了继续这一有希望的研究路线，以更好地了解与异位脂肪沉积相关的病理生理学，我们建议研究脂滴表面蛋白控制非成脂细胞和组织中脂肪分解的功能和机制，以及作为肥胖这些病理生理后果的根本原因的脂滴成分和活性的潜在变化，并潜在地作为治疗干预的新的生化途径。在健康状态下，脂滴通过将任何多余的非酯化脂肪酸(NEFA)储存为甘油三酯(TAG)并在需要时释放它，来维持细胞非酯化脂肪酸(NEFA)的动态平衡。这种将过量的NEFA降至最低的能力被认为可以提供保护，防止“脂毒性”，其特征是胰岛素抵抗导致炎症，在极端情况下还会导致细胞凋亡。此外，NEFA的储存和释放途径都涉及二酰甘油酯(DAG)的中间产物，DAG也具有信号转导功能。这是可能的，通过不受调节的脂肪分解增加DAG的产生可能在与异位脂肪相关的不良反应中起作用。因此，调控脂滴储存和释放NEFA是异位脂肪致病机制的有力候选者。尽管对脂滴的调节仍然知之甚少，但大量研究表明，PAT蛋白家族中的一个或多个成员似乎总是与脂滴表面有关，其中一个是Perilipin，已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蛋白组成，具有较高的初级序列，与载脂蛋白相似，有些是组织特异性的。因此，本研究的总体目标是了解在非成脂组织中表达的三种功能未知的PAT蛋白：adrp、TIP47和PAT-1(或MLDP)的病理生理学意义。根据我们的初步结果，这些蛋白质是调节非成脂组织中脂滴脂解的有力候选者，它们的功能障碍可能是异位脂肪介导的胰岛素抵抗的原因。这些拟议的研究将检验这一假设，如果正确，将为疾病预防或治疗干预提供一种方法。