Regulation of adipose lipid metabolism by new lipid droplet protein

新型脂滴蛋白调控脂肪脂质代谢

• 批准号: 10180263
• 负责人: Hei Sook Sul
• 金额: $ 33.17万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180263
• 关键词: Adipocytes; Adipose tissue; Apolipoproteins; Body fat; CRISPR/Cas technology; Cells; Code; Diabetes Mellitus; Diet; Disease Management; Energy Metabolism; Fasting; Future; Gene Expression; Genetic; Glucose; Goals; Growth; Health; High Fat Diet; Homeostasis; Insulin; Knock-out; Knockout Mice; Lipase; Lipids; Lipolysis; Liver; Metabolic syndrome; Metabolism; Molecular; Morphology; Mus; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peptide Signal Sequences; Physiological; Physiology; Play; Protein Family; Proteins; Regulation; Research; Role; Site; Structure; System; Tissues; Transgenic Mice; Triglyceride Metabolism; Triglycerides; adipocyte differentiation; diabetes control; feeding; gain of function; in vivo; lipid biosynthesis; lipid metabolism; lipid transfer protein; new therapeutic target; overexpression; protein function; therapeutic target

We recently identified a previously uncharacterized 38 kD protein, which contains an apolipoprotein-like domain and is specifically expressed in adipose tissue. Due to lack of signal sequence, however, the protein is not secreted. Rather, we found that it is localized to lipid droplets (LD), making this protein a newly discovered adipose-specific LD-associated protein. We found that this new LD-associated protein is found at the LD contact site and promotes lipid transfer. In addition, we detected direct interaction with Fsp27 (also called CideC). Furthermore, expression of the gene coding for this apolipoprotein-like protein is very low in adipose tissue of fasted mice, but is increased upon feeding, especially when fed a high fat diet. We also found it to be overexpressed in both genetic and diet induced obesity, suggesting its contribution to adiposity. We have generated transgenic mice for overexpression in adipose tissue, as well as global KO mice by using CRISPR-Cas9 system. Our transgenic mice showed a greatly increased white adipose tissue (WAT) mass with enlarged adipocytes in WAT, having decreased lipolysis without significant changes in lipogenesis. Conversely, our global KO mice showed a substantially diminished adipose tissue mass with smaller adipocyte size with higher lipolysis that protected mice from diet induced obesity. Our long-term goal is to understand the molecular details and physiological significance of the function of this protein as a LD-associated protein to promote LD growth/lipid transfer and TAG storage in WAT. Aim 1 is to examine regulation of lipid transfer by ApoL6. Aim 2 is to examine regulation of lipolysis by this protein. Finally, Aim 3 is to examine its role in vivo by performing loss- and gain-of function studies in mice. Overall, the proposed research will define the role of this newly discovered LD protein on LD growth/lipid transfer and lipolysis in WAT. This research may not only help to better understand adipose LD physiology but also provide future therapeutic targets for obesity/diabetes.

我们最近发现了一个以前未知的38 kD蛋白，其中包含一个载脂蛋白样结构域，并在脂肪组织中特异性表达。然而，由于缺乏信号序列，蛋白质不被分泌。相反，我们发现它定位于脂滴（LD），使该蛋白成为新发现的脂肪特异性LD相关蛋白。我们发现这种新的LD相关蛋白存在于LD接触位点，并促进脂质转移。此外，我们检测到与Fsp 27（也称为CideC）的直接相互作用。此外，编码这种载脂蛋白样蛋白的基因的表达在禁食小鼠的脂肪组织中非常低，但在喂食时增加，特别是当喂食高脂肪饮食时。我们还发现它在遗传和饮食诱导的肥胖中过表达，表明它对肥胖的贡献。我们已经通过使用CRISPR-Cas9系统产生了用于在脂肪组织中过表达的转基因小鼠，以及全球KO小鼠。我们的转基因小鼠表现出白色脂肪组织（WAT）质量大大增加，WAT中的脂肪细胞增大，脂解减少，脂肪生成无显著变化。相反，我们的整体KO小鼠显示脂肪组织质量显著减少，脂肪细胞尺寸较小，脂解较高，保护小鼠免受饮食诱导的肥胖。我们的长期目标是了解这种蛋白作为LD相关蛋白的功能的分子细节和生理意义，以促进LD生长/脂质转移和TAG在WAT中的储存。目的1是检查ApoL 6对脂质转移的调节。目的2是检测该蛋白对脂解的调节作用。最后，目的3是通过在小鼠中进行功能丧失和获得研究来检查其在体内的作用。总的来说，拟议的研究将确定这种新发现的LD蛋白对WAT中LD生长/脂质转移和脂解的作用。这项研究不仅有助于更好地了解脂肪LD生理学，而且还为肥胖/糖尿病提供了未来的治疗靶点。