Mechanisms of lipid droplet organization and functional diversification

脂质储存细胞（如脂肪细胞）对于维持机体内稳态至关重要，它们可以在循环脂肪酸（FAs）以甘油三酯（TG）的形式储存在细胞质脂滴（ld）之前有效地吸收它们。脂质摄取、储存或输出缺陷导致血液循环FAs升高和非脂肪组织脂肪堆积，最终导致代谢性疾病，包括肥胖、心血管疾病和2型糖尿病（T2D）。尽管脂肪储存细胞在空间和时间上如何协调脂肪酸的吸收、储存和动员是其功能的核心，但仍然是一个谜，但对于理解人类健康和疾病中的脂质储存至关重要。我的实验室最近描述了一个蛋白质家族，该家族通过定义内质网（ER）内的子结构域来协调ld的空间组织，ld从中萌发（Hariri， EMBO报告，2017;Hariri， JCB, 2019; Ugrankar, Dev Cell, 2019; Datta， JCB, 2019）。通过果蝇研究，我们发现其中一种蛋白质Snz定位于脂肪细胞内质膜（PM）接触处，并促进细胞周围LD的生物发生（Ugrankar, Dev cell, 2019）。我们认为内质网，PM和LD在脂肪细胞周围功能偶联，为FA加工和LD生物形成提供了一个独特的亚细胞环境，靠近细胞表面。该项目将剖析Snz及其人类同源Snx14在FA去饱和和TG合成中的作用（目的1），以及表征果蝇脂肪细胞内调节LD空间组织的分子决定因素（目的2）。最后，我们将分析ld是如何在哺乳动物细胞周围产生的，以响应代谢线索，如脂肪分解和FA吸收，并使用小鼠模型系统询问Snx14在这一过程中的作用（Aim 3）。总的来说，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ld提供新的机制见解。这项工作为脂肪细胞、肝细胞和泌乳细胞等脂质储存和分泌细胞的功能提供了机制见解，并增强了我们对代谢综合征（如T2D）的理解。Snx14与小脑共济失调病SCAR20有关，这项工作为SCAR20背后的脂质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.