Mechanisms of lipid droplet organization and functional diversification

脂肪细胞等储脂细胞是维持机体内环境稳定所必需的，可以有效地吸收循环脂肪酸(FAs)，然后以甘油三酯(TG)的形式储存在细胞质脂滴(LDs)中。脂肪摄取、储存或输出方面的缺陷会导致血液循环中FAs的增加和非脂肪组织中的脂肪积聚，最终导致包括肥胖、心血管疾病和2型糖尿病(T2D)在内的代谢性疾病。尽管脂肪储存细胞是其功能的中心，但脂肪储存细胞如何在空间和时间上协调FA的吸收、储存和动员仍然是一个谜，但对于理解人类健康和疾病中的脂肪储存是关键的。我的实验室最近表征了一系列蛋白质，这些蛋白质通过定义内质网(ER)中的亚域来协调LDS的空间组织(Hariri，EMBO报告，2017；Hariri，JCB，2019；Urankar，Dev Cell，2019；Datta，JCB，2019)。以果蝇为例，我们证明了其中一种名为SNZ的蛋白质定位于脂肪细胞的ER-质膜(PM)接触，并促进细胞外围的LD生物发生(Urankar，Dev Cell，2019)。我们认为ER、PM和LDS在脂肪细胞外周功能上偶联，为FA加工和细胞表面附近的LD生物发生提供了独特的亚细胞环境。本项目将剖析SNZ及其人类同源基因Snx14在脂肪酸去饱和和甘油三酯合成中的作用(目标1)，并表征调控果蝇脂肪细胞内LD空间组织的分子决定因素(目标2)。最后，我们将剖析LDS是如何在哺乳动物细胞的外围产生的，以响应脂肪分解和FA吸收等代谢信号，并使用小鼠模型系统询问Snx14在这一过程中的作用(目标3)。总而言之，这项工作将为果蝇和哺乳动物脂肪储存细胞在特定代谢线索中如何产生、空间组织和利用LDS提供新的机械性见解。这项工作提供了对脂肪细胞、肝细胞和乳汁分泌细胞等储脂和分泌细胞功能的机械性见解，并增强了我们对T2D等代谢综合征的理解。Snx14与小脑性共济失调疾病SCAR20有关，这项工作为了解SCAR20背后的脂代谢缺陷提供了新的机制见解。

Lipid-storing cells such as adipocytes are essential for maintaining organismal homeostasis, and can efficiently absorb circulating fatty acids (FAs) prior to their storage as triglycerides (TG) in cytoplasmic lipid droplets (LDs). Defects in lipid uptake, storage, or export lead to elevated blood-circulating FAs and fat buildup in non-adipose tissues, ultimately contributing to metabolic diseases including obesity, cardiovascular disease, and type 2- diabetes (T2D). Although central to their function, how fat-storing cells spatially and temporally coordinate FA absorption, storage, and mobilization remains enigmatic, yet central to the understanding of lipid storage in human health and disease. My lab recently characterized a family of proteins that coordinate the spatial organization of LDs by defining sub-domains within the endoplasmic reticulum (ER) from which LDs bud (Hariri, EMBO reports, 2017; Hariri, JCB, 2019; Ugrankar, Dev Cell, 2019; Datta, JCB, 2019). Using Drosophila, we showed that one such protein, Snz, localizes to adipocyte ER-plasma membrane (PM) contacts and promotes LD biogenesis in the cell periphery (Ugrankar, Dev Cell, 2019). We propose that the ER, PM, and LDs are functionally coupled in the adipocyte cell periphery, providing a unique sub-cellular environment for FA processing and LD biogenesis adjacent to the cell surface. This project will dissect the role of Snz and its human ortholog Snx14 in FA desaturation and TG synthesis (Aim 1), as well as characterize the molecular determinants that regulate LD spatial organization within Drosophila adipocytes (Aim 2). Finally, we will dissect how LDs are generated in the periphery of mammalian cells in response to metabolic cues such as lipolysis and FA absorption, and interrogate the role of Snx14 in this process using a murine model system (Aim 3). Collectively this work will provide new mechanistic insights into how LDs are produced, spatially organized, and utilized during specific metabolic cues in both Drosophila and mammalian fat-storing cells. The work provides mechanistic insights into the functions of lipid-storing and secreting cells such as adipocytes, hepatocytes, and milk-secreting cells, as well as enhances our understanding of metabolic syndromes such as T2D. Snx14 is linked to the cerebellar ataxia disease SCAR20, and this work provides new mechanistic insights into the lipid metabolism defects underlying SCAR20.