A Simple Cellular Model for Lipodystrophy

描述（由申请人提供）：众所周知，脂肪组织过多会增加患心脏病、中风和糖尿病的风险；肥胖通常是由摄入过多的热量引起的。很少有人意识到脂肪营养不良对健康的破坏性影响。在最严重的情况下，脂肪组织几乎不存在，脂肪异常地储存在肝脏和肌肉中，甘油三酯和游离脂肪酸的循环水平大幅增加。代谢性疾病包括糖尿病和坦率的器官衰竭，往往是结果。中性脂肪通常储存在脂质体中，这在脂肪细胞中最为明显，但这些细胞器的起源是神秘的，没有已知的催化它们组装的因素被确定。我们认为脂质体的组装和/或维持缺陷是脂质营养不良的一个原因。对异常脂质体的酵母基因组筛选（基因缺失菌株的观察）揭示了62个参与脂质体组装或维持的基因，其中3个已知会导致人类或小鼠的脂质营养不良。我们将研究与脂肪营养不良有关的基因的功能，特别是导致严重人类疾病的seipin突变。我们将确定seipin是否存在于内质网的脂体出口位点，以及它是否可能组织这些位点。我们将研究小鼠脂肪营养不良基因lipin及其激活因子，并确定它们是否参与脂质体的脂质和蛋白质的包装。我们的筛选还检测到17个涉及细胞器运输的基因，特别是涉及核内体的基因。我们将研究其中的三组，因为它们与脂质体组装中涉及的因子的逆行运输或维持脂质体所需的可能的内体通讯有关。综上所述，我们的筛选已经发现了影响脂质体的新因子，我们将研究其中的一些因子，特别是seipin，以开始阐明脂质体组装和维持的步骤。这一信息对脂肪营养不良症和肥胖症应该是有用的，它可能在设计治疗这些毁灭性疾病的新形式方面证明是有价值的。

DESCRIPTION (provided by applicant): The increased risk of developing heart disease, strokes, and diabetes with excess adipose tissue is well known; obesity is generally caused by excess caloric intake. Less well appreciated are the devastating effects on health of the lipodystrophies. In the most severe forms, adipose tissue is virtually nonexistent, fat is abnormally stored in the liver and muscle, and there is a huge increase in circulating levels of triglycerides and free fatty acids. Metabolic diseases including diabetes, and frank organ failure, often are the results. Neutral fat is normally stored in lipid bodies, which are most apparent in adipocytes, yet the origin of these organelles is mysterious and no known factors that catalyze their assembly have been identified. We propose that defects in assembly and/or maintenance of lipid bodies are a cause of lipodystrophy. A yeast genomic screen for aberrant lipid bodies (observation of gene deletion strains) has revealed 62 genes involved in lipid body assembly or maintenance, three of which are known to cause lipodystrophy in humans or mice. We will study the function of the genes involved in lipodystrophy, particularly seipin, mutations in which cause severe human disease. We will determine if seipin is found at lipid body exit sites of the endoplasmic reticulum and whether it might organize these sites. We will study the murine lipodystrophy gene lipin and its activators, and determine if they are involved in packaging of lipid and protein for lipid bodies. Our screen also detected 17 genes involved in organelle trafficking, especially involving endosomes. We will study three groups of these as they relate to possible roles in retrograde transport of factors involved in lipid body assembly, or possible endosomal communication required for maintenance of lipid bodies. In summary, novel factors for lipid bodies have been identified by our screen and we shall study several of them, especially seipin, to begin to elucidate the steps of lipid body assembly and maintenance. This information should be useful in the lipodystrophies and obesity, and it may prove valuable in the design of novel forms of therapy for these devastating diseases. PUBLIC HEALTH RELEVANCE: Both an absence of fat tissue and an overabundance of fat tissue are major risk factors for heart disease, strokes, diabetes, and organ failure. Fat is stored in cell organelles called lipid bodies, yet how they are formed is a mystery, and what goes wrong in lipodystrophy (absence of fat tissue) is often not clear. Experiments are proposed to understand how lipid bodies are formed and what goes wrong in two types of lipodystrophy.