Lipid storage is a fundamental process for organisms to buffer fluctuations in the availability and need for metabolic energy. Lipids are predominantly stored as neutral lipids, such as triacylglycerols (TGs), in organelles called lipid droplets (LDs). In conditions of excess metabolic energy, cells convert carbohydrates to fatty acids and esterify them, along with dietary fatty acids, to glycerol-3-phosphate to form TG. Conversely, when fatty acids are needed as metabolic fuel or as precursors for membrane components, TGs are hydrolyzed. Whether or not cells have lipid stores directly impacts their ability to grow and divide, as well as their physiology and need to import nutrients. Through a combination of unbiased genetic and biochemical screens, we recently found that all members of the MLX family of transcription factors localize to the LD surfaces as LDs accumulate in cells. These transcription factors include MLX and its obligate dimerization partners, MLXIP/MondoA or MLXIPL/MondoB/ChREBP, which detect glucose derivatives and are key regulators of glucose and lipid metabolism. Deficiency of ChREBP has also been linked to the developmental disorder Williams-Beuren syndrome and to features of the metabolic syndrome. Based on extensive preliminary data, we suggest a model in which the accumulation of LDs serves to attenuate the transcriptional response of MLX:ChREBP or MLX:MondoA targets in response to glucose. We will test this model defining the mechanism and regulation of MLX-type transcription factor targeting to LDs and elucidating how this modulates their response to glucose. Completing these aims will reveal a fundamental aspect of metabolic coordination through a fascinating, novel paradigm of transcriptional control. It may also have important implications for human health. Overaccumulation of LDs is the hallmark of metabolic disease linked to obesity, a problem of pandemic proportions. Our findings will shed new light on physiological sequelae of LD accumulation, possibly providing therapeutic avenues for intervention.
Whether and how cells detect and respond to the presence of lipid stores is largely unknown. Here we define how factors modulating gene expression bind to cellular lipid droplets, and how such sequestration alters their response to available glucose in the medium. Because this gene expression network is of broad importance to mammalian metabolism, these findings will have a broad impact on our understanding of the consequences of cellular lipid accumulation.
