A Simple Cellular Model for Lipodystrophy

脂肪营养不良的简单细胞模型

• 批准号: 7440577
• 负责人: JOEL M GOODMAN
• 金额: $ 30.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440577
• 关键词: 3T3-L1 Cells; Acyl Coenzyme A; Adipocytes; Adipose tissue; Affect; BSCL2 gene; Binding Proteins; Biological Assay; Cell model; Cells; Class; Co-Immunoprecipitations; Communication; Complex; Cytolysis; Cytoplasm; Defect; Diabetes Mellitus; Diffuse; Disease; Disruption; Dyslipidemias; Electron Microscopy; Endoplasmic Reticulum; Endosomes; Energy Intake; Enzymes; Fatty Liver; Fatty acid glycerol esters; Gene Deletion; Genes; Genomics; Golgi Apparatus; Health; Heart Diseases; Human; Insulin Resistance; Life; Lipase; Lipids; Lipodystrophy; Liver; Maintenance; Membrane; Metabolic Diseases; Mus; Muscle; Mutate; Mutation; Nonesterified Fatty Acids; Obesity; Organ failure; Organelles; Pathway interactions; Personal Satisfaction; Process; Proliferating; Proteins; Public Health; Risk; Risk Factors; Role; Site; Stroke; Surface; Syndrome; Testing; Tissues; Triglycerides; Vacuole; Vesicle; Work; Yeasts; cellular imaging; design; falls; fatty acid oxidation; gene function; human disease; lipid transport; lipine; luminal membrane; novel; peroxisome; promoter; research study; retrograde transport; stem; trafficking; vacuolar H+-ATPase

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.

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;肥胖通常是由热量摄入过多引起的。不太了解的是脂肪代谢障碍对健康的破坏性影响。在最严重的形式中，脂肪组织几乎不存在，脂肪异常地储存在肝脏和肌肉中，并且甘油三酯和游离脂肪酸的循环水平大幅增加。包括糖尿病在内的代谢性疾病和明显的器官衰竭往往是其结果。中性脂肪通常储存在脂质体中，这在脂肪细胞中最明显，但这些细胞器的起源是神秘的，并且没有已知的催化它们组装的因子。我们建议，在组装和/或维护脂质体的缺陷是脂肪营养不良的原因。异常脂质体的酵母基因组筛选（观察基因缺失菌株）揭示了62个参与脂质体组装或维持的基因，其中三个已知会导致人类或小鼠的脂肪营养不良。我们将研究与脂肪代谢障碍有关的基因的功能，特别是引起严重人类疾病的seipin突变。我们将确定是否seipin被发现在脂质体出口网站的内质网，以及它是否可能组织这些网站。我们将研究小鼠脂肪代谢障碍基因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包装。我们的筛选还检测到17个基因参与细胞器运输，特别是涉及内体。我们将研究其中的三组，因为它们涉及到可能的作用，参与脂质体组装，或可能的内体通信所需的脂质体的维护的因素逆行运输。总之，通过我们的筛选，已经鉴定了脂质体的新因子，我们将研究其中的几个，特别是seipin，以开始阐明脂质体组装和维持的步骤。这些信息应该是有用的脂肪代谢障碍和肥胖症，它可能被证明是有价值的设计新形式的治疗这些毁灭性的疾病。 公共卫生相关性：缺乏脂肪组织和脂肪组织过多都是心脏病、中风、糖尿病和器官衰竭的主要危险因素。脂肪储存在称为脂质体的细胞器中，但它们是如何形成的是一个谜，脂肪代谢障碍（缺乏脂肪组织）的问题往往不清楚。提出实验来了解脂质体是如何形成的，以及在两种类型的脂肪代谢障碍中出现了什么问题。