Regulation of adipose lipid metabolism by new lipid droplet protein

我们最近发现了一个以前未被鉴定的38 kD蛋白，它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，该蛋白不分泌。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接触部位并促进脂质转移。此外，我们检测到与Fsp27（也称为CideC）的直接相互作用。此外，这种载脂蛋白样蛋白编码基因的表达在禁食小鼠的脂肪组织中非常低，但在喂食后增加，特别是在喂食高脂肪饮食时。我们还发现它在遗传和饮食引起的肥胖中都过度表达，这表明它对肥胖有贡献。我们利用CRISPR-Cas9系统在脂肪组织中产生过表达转基因小鼠，以及全球KO小鼠。我们的转基因小鼠显示白色脂肪组织（WAT）团块大大增加，WAT中脂肪细胞增大，脂肪分解减少，但脂肪生成没有明显变化。相反，我们的全球KO小鼠显示脂肪组织质量显著减少，脂肪细胞大小较小，脂肪分解程度较高，保护小鼠免受饮食引起的肥胖。我们的长期目标是了解该蛋白作为LD相关蛋白在WAT中促进LD生长/脂质转移和TAG储存的分子细节和功能的生理意义。目的1：探讨ApoL6对脂质转移的调控作用。目的2是检查该蛋白对脂肪分解的调节。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，本研究将明确该新发现的LD蛋白在WAT中LD生长/脂质转移和脂质分解中的作用。这项研究不仅有助于更好地理解脂肪性LD的生理机制，也为肥胖症/糖尿病的治疗提供了新的靶点。

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.