Mechanisms of lipid droplet organization and functional diversification

贮脂细胞如脂肪细胞对于维持生物体内平衡是必不可少的，并且可以在循环脂肪酸（FA）作为甘油三酯（TG）储存在细胞质脂滴（LD）中之前有效地吸收它们。脂质摄取、储存或输出的缺陷导致血液循环FA升高和非脂肪组织中的脂肪积聚，最终导致代谢疾病，包括肥胖、心血管疾病和2型糖尿病（T2 D）。尽管脂肪储存细胞的功能至关重要，但脂肪储存细胞如何在空间和时间上协调脂肪酸的吸收、储存和动员仍然是个谜，但对于理解人类健康和疾病中的脂质储存至关重要。我的实验室最近表征了一个蛋白质家族，该蛋白质家族通过定义内质网（ER）内的子域来协调LD的空间组织，LD从内质网（ER）中萌芽（Hariri，EMBO报告，2017; Hariri，JCB，2019; Ugrankar，Dev Cell，2019; Datta，JCB，2019）。使用果蝇，我们发现一种这样的蛋白质Snz定位于脂肪细胞ER-质膜（PM）接触并促进细胞周边的LD生物合成（Ugrankar，Dev Cell，2019）。我们认为ER、PM和LD在脂肪细胞外周中功能性偶联，为FA加工和LD在细胞表面附近的生物合成提供了独特的亚细胞环境。该项目将剖析Snz及其人类直系同源物Snx 14在FA去饱和和TG合成中的作用（目标1），以及表征调节果蝇脂肪细胞内LD空间组织的分子决定因素（目标2）。最后，我们将剖析LD是如何在哺乳动物细胞的外周产生的代谢线索，如脂解和FA吸收，并询问Snx 14在这一过程中使用小鼠模型系统的作用（目的3）。总的来说，这项工作将提供新的机制的见解，LD是如何产生的，空间组织，并利用特定的代谢线索在果蝇和哺乳动物的脂肪储存细胞。这项工作为脂肪细胞、肝细胞和乳汁分泌细胞等脂质储存和分泌细胞的功能提供了机制性见解，并增强了我们对T2 D等代谢综合征的理解。Snx 14与小脑共济失调疾病SCAR 20有关，这项工作为SCAR 20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.