The role of FSP27b on dietary lipid absorption, lipoprotein secretion, and oxidative metabolism

FSP27b 对膳食脂质吸收、脂蛋白分泌和氧化代谢的作用

• 批准号: 10552559
• 负责人: Angel Baldan
• 金额: $ 34.09万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552559
• 关键词: Acceleration; Address; Adipocytes; Agonist; Amendment; Antisense Oligonucleotides; Area; Attention; Basic Science; Biochemical; Bioenergetics; Biogenesis; Biological Assay; Biology; Blood; Brown Fat; Cardiac Myocytes; Cardiometabolic Disease; Cardiovascular Diseases; Catabolism; Cell Respiration; Cells; Chylomicrons; Clinical; Clinical Sciences; Cultured Cells; Data; Diet; Dietary Fats; Disease; Drug or chemical Tissue Distribution; Dyslipidemias; Energy Metabolism; Equilibrium; Familial partial lipodystrophy; Fasting; Fatty Acids; Future; Genes; Genetic; Genetic Polymorphism; Goals; Hepatic; Hepatocyte; High Prevalence; Homeostasis; Human; Hyperlipidemia; Incidence; Insulin Resistance; Intervention; Intestines; Knowledge; Label; Laboratories; Lead; Lipids; Lipoproteins; Liver; LoxP-flanked allele; Mediating; Medical; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Muscle; Muscle Fibers; Norepinephrine; Nutritional; Obesity; Organ; Pathologic; Pathway interactions; Patients; Pattern; Peripheral; Peroxisome Proliferator-Activated Receptors; Physiological; Physiology; Plasma; Population; Protein Isoforms; Proteins; Public Health; Publishing; Reporting; Research; Rest; Risk; Role; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissue Transplantation; Tissues; Transgenic Organisms; Transplantation; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; Work; absorption; base; cardiovascular risk factor; circadian; diet-induced obesity; experimental study; fatty liver disease; frontier; gain of function; human disease; improved; in vivo; in vivo monitoring; innovation; intestinal epithelium; knock-down; lipid metabolism; loss of function; loss of function mutation; mouse model; neglect; new therapeutic target; novel; obesity treatment; overexpression; oxidation; pharmacologic; response; success

SUMMARY The proposed work will define the role of the lipid droplet-associated protein CIDEC (also known as FSP27) on the metabolic fate of lipids in liver and intestine, circulating lipoproteins, and oxidative lipid metabolism in muscle and brown adipose tissue (BAT). Dysregulation of lipid metabolism is the basis of some of the most common medical disorders in Western populations, such as cardiovascular disease, hyperlipidemia, fatty liver diseases, obesity, and insulin resistance. The long-term goal in our laboratory is to elucidate molecular and cellular mechanisms governing whole-body lipid homeostasis, both under physiological and pathological conditions. CIDEC/FSP27 encodes 2 isoforms, a and b, with strict tissue distribution. Here we will exploit Fsp27bKO mice to reveal the role of FSP27b (the sole FSP27 expressed in liver and intestine, and the major isoform in BAT) on the partitioning of lipids for storage/oxidation/secretion. We will test the new ideas that FSP27b is a critical regulator of hepatic APOB lipidation and secretion, dietary lipid absorption and postprandial lipemia, and fatty acid utilization in peripheral tissues. The proposed studies will be transformative for our understanding of: i) mechanisms governing the biogenesis and secretion of pro-atherogenic lipoproteins; ii) lipid biology in major oxidative tissues; and iii) metabolic cross-talk between liver and other tissues, an area that has been largely neglected in the past. To achieve the goal of defining the role of FSP27b on lipid metabolism, we plan three specific aims. Aim 1 will test the hypothesis that FSP27b promotes the lipidation and secretion of APOB-containing lipoproteins in liver and intestine. Aim 2 will test the hypothesis that hepatic FSP27b limits the availability of PPAR agonists for peripheral tissues. Aim 3 will test the hypothesis that FSP27b reduces energy expenditure in brown adipose tissue. Importantly, some of the proposed research will correct the published scientific record on FSP27, which is based on a flawed “Fsp27-floxed” mice. The translational relevance of our studies is highlighted by reports showing that polymorphisms in FSP27 are associated with elevated fasting triglyceridemia in humans, and that loss-of- function mutations result in familial partial lipodystrophy, type 5 (FPLD5). Overall, success of the proposed studies will fill a large gap of knowledge in whole-body lipid (patho)physiology, by defining molecular mechanisms of lipid droplet-mediated control of triglyceride metabolism in liver, intestine, muscle, and brown adipose tissue, with particular attention to multi-organ metabolic cross-talk via circulating lipids. These studies may also establish FSP27 as a valid pharmacological target to manage fatty liver diseases, diet-induced obesity, dyslipidemias, and cardiovascular risk in patients.

概括 提出的工作将定义脂质液滴相关蛋白CIDEC（也称为FSP27）的作用 肝脏和肠中脂质的代谢命运，循环脂蛋白以及肌肉中氧化脂质代谢 和棕色脂肪组织（蝙蝠）。脂质代谢失调是一些最常见的基础 西方人群的医学疾病，例如心血管疾病，高脂血症，脂肪肝疾病， 肥胖和胰岛素抵抗。我们实验室的长期目标是阐明分子和细胞 在物理和病理状况下，控制全身脂质稳态的机制。 CIDEC/FSP27编码2种同工型A和B，具有严格的组织分布。在这里，我们将利用FSP27BKO小鼠 揭示FSP27B（唯一在肝脏和肠中表达的唯一FSP27，以及BAT中的主要同工型）在 脂质分配用于存储/氧化/分泌的脂质。我们将测试FSP27B是关键的新想法 肝APOB脂质和分泌，饮食脂质抽象和餐后脂肪血症和脂肪的调节剂 外周组织中的酸利用。拟议的研究将是我们对：i的理解的变革性的。 促动脉粥样硬化脂蛋白的生物发生和分泌的机制； ii）主要的脂质生物学 氧化组织； iii）肝脏和其他组织之间的代谢串扰，这个区域在很大程度上是 过去被忽视。 为了实现定义FSP27B在脂质代谢中的作用的目标，我们计划了三个具体目标。目标1意志 测试FSP27B促进肝脏中含APOB的脂蛋白的脂化和分泌的假设 和肠。 AIM 2将检验以下假设：肝FSP27B限制PPAR激动剂的可用性 外围组织。 AIM 3将检验以下假设：FSP27B减少棕色脂肪的能量消耗 组织。 重要的是，一些拟议的研究将纠正FSP27上已发表的科学记录，该记录基于 在有缺陷的“ fsp27 lo-lox”小鼠上。我们研究的翻译相关性由显示的报告强调了 FSP27中的多态性与人类禁食甘油三酯血症的升高有关，并且丧失 - 功能突变导致家族性部分脂肪营养不良，5型（FPLD5）。总体而言，提议的成功 研究将通过定义分子机制来填补全身脂质（PATHO）生理学的大量知识。 脂质液滴介导的对肝脏，肠，肌肉和棕色脂肪组织中甘油三酸酯代谢的控制的控制 特别关注通过循环脂质的多器官代谢串扰。这些研究也可能确定 FSP27是管理脂肪肝疾病，饮食引起的肥胖症，血脂异常和 患者的心血管风险。