Systematic genome perturbation reveals coordination of lipid droplets and metabolic gene regulation

Lipid droplets (LDs) store lipids for metabolic eneergy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in human macrophages, a cell type relevant to metabolic diseases. Among ~550 genes regulating lipid storage, we identify MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates multiple metabolic processes. We show that MLX and family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs increase in cells, LD binding of MLX, MLXIP/MondoA, and MLXIPL/ChREBP reduces their transcriptional activity, whereas the absence of LDs results in hyperactivation. Our findings uncover an unexpected component to a lipid storage response, in which binding of MLX transcription factors to the LD surface modulates their activity, adjusting the expression of metabolic genes to lipid storage levels.