Physiology of Lipid Droplets and Triglyceride Storage

脂滴和甘油三酯储存的生理学

• 批准号: 8888803
• 负责人: ROBERT V FARESE
• 金额: $ 56.73万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888803
• 关键词: Caliber; Cells; Cirrhosis; Comorbidity; Cultured Cells; Development; Diabetes Mellitus; Disease; Disease Pathway; Disease Progression; Drug Metabolic Detoxication; Drug Targeting; Enzymes; Evolution; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genetic Models; Heart Diseases; Hepatic; Hepatocyte; Hypertriglyceridemia; Individual; Insulin Resistance; Label; Light; Link; Lipids; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Pathway interactions; Pharmacologic Substance; Physiologic pulse; Physiological; Physiology; Population; Process; Protein Isoforms; Public Health; Relative (related person); Research; Source; Stable Isotope Labeling; Steatohepatitis; Study models; Surface; System; Testing; Tissues; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; Wild Type Mouse; cell type; diabetic; fly; insight; lipid biosynthesis; lipid metabolism; mortality; non-alcoholic fatty liver; overexpression; pandemic disease; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Diseases of metabolic excess constitute the most prominent "killers" in the developed world. At the heart of these diseases lies excessive storage of triacylglycerols (triglycerides, TG), which gives rise to obesity, lipotoxicity, and associated o-morbidities, such as non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). TGs are stored in cytosolic lipid droplets (LDs). Our research recently revealed two distinct classes o LDs: smaller LDs (sLD) and larger and more heterogeneous expanding LDs (eLDs). LDs of the latter class grow by local TG synthesis on the LD surface, mediated by isoforms of TG synthesis enzymes, such as GPAT4 and DGAT2. We discovered that these different LD populations are present in nearly all types of cells. However, their relative contributions to TG storage and secretion in tissues are unknown, as are their functions in physiology and metabolism. Here we propose experiments in murine hepatocytes and liver that will elucidate the functions of eLDs and sLDs in hepatic TG metabolism. We hypothesize that eLDs, conserved throughout evolution, represent the first tier of TG storage: eLD formation allows LDs to expand to a large size, accommodating the majority of synthesized TG in cells and segregating lipids from other lipid metabolic pathways and ER functions. When the capacity of eLDs for TG storage is overwhelmed, sLDs form and provide a second line of defense by esterifying these molecules. To test this model for the function of different LD classes, we will determine the physiological function of eLDs and sLDs by determining a) the relative contributions of the eLD and sLD pathways to LD formation and TG storage in hepatocytes, b) the requirements of the eLD and sLD pathways for TG secretion (as components of very low-density lipoproteins, or VLDL) in the liver, and c) the relative contributions of the eLD and sLD pathways to the development of NAFLD and NASH in the liver. Our results will provide the first insights of how different LD classes function to store or secrete TG. Moreover, they will shed light on which of these different LD classes are important for preventing the development of NASH in the setting of NAFLD. Insights from these studies should provide new information for pharmaceutical targeting of drugs to treat diseases of TG excess, such as hepatic steatosis and VLDL-related hypertriglyceridemia.

描述（由申请人提供）：代谢过度疾病是发达国家最突出的“杀手”。这些疾病的核心是三酰甘油（甘油三酯，TG）的过度储存，导致肥胖、脂肪毒性和相关的o-发病率，如非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）。tg储存在细胞质脂滴（ld）中。我们的研究最近揭示了两种不同类型的ld：较小的ld （sLD）和较大且更异构的扩展ld （eld）。后一类的LD是由TG合成酶的异构体GPAT4和DGAT2介导，通过LD表面的局部TG合成来生长的。我们发现这些不同的LD群体存在于几乎所有类型的细胞中。然而，它们在组织中对TG储存和分泌的相对贡献是未知的，它们在生理和代谢中的功能也是未知的。在此，我们提出在小鼠肝细胞和肝脏中进行实验，以阐明eld和sLDs在肝脏TG代谢中的功能。我们假设，在整个进化过程中保守的eLD代表了TG储存的第一层：eLD的形成允许ld扩展到大尺寸，容纳细胞中大部分合成的TG，并从其他脂质代谢途径和内质网功能中分离脂质。当用于TG存储的eld的容量被淹没时，通过将这些分子酯化形成sld并提供第二道防线。为了测试这个模型不同的LD类的函数,我们将决定古人的生理功能和sLD确定)的相对贡献古人和sLD LD和TG存储路径在肝细胞,b)的要求古人和TG sLD途径分泌(作为组件的低密度脂蛋白,或VLDL)在肝脏,和c)的相对贡献古人和sLD通路的发展非酒精性脂肪肝和纳什在肝脏。我们的研究结果将首次揭示不同的LD类如何储存或分泌TG。此外，它们将揭示这些不同的