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.
Dietary lipids must be properly stored within adipocyte lipid droplets (LDs) to maintain health, and defects in lipid storage are associated with metabolic syndromes including obesity, cardiovascular disease, and type 2 diabetes. This project capitalizes on our recent work in Drosophila where we discovered a highly conserved protein called Snz that connects LDs to the plasma membrane of adipocytes, thus regulating lipid exchange with extracellular lipid pools at the cell periphery. Accomplishing the aims will provide new mechanistic insights into how adipocytes and other fat-storing cells coordinate lipid storage with mobilization during metabolic cues, as well as how cells properly organize fat stores to maintain homeostasis.
