Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression

• Published in: Molecular cell 2020-03, Vol.77 (6), p.1251-1264.e9
• Main Authors: Mejhert, Niklas, Kuruvilla, Leena, Gabriel, Katlyn R., Elliott, Shane D., Guie, Marie-Aude, Wang, Huajin, Lai, Zon Weng, Lane, Elizabeth A., Christiano, Romain, Danial, Nika N., Farese, Robert V., Walther, Tobias C.
• Format: Article
• Language: English
• Subjects: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Cells, Cultured; ChREBP; Gene Expression Regulation; Genetic Testing; glucose; Glucose - metabolism; Humans; lipid droplets; Lipid Droplets - metabolism; Macrophages - cytology; Macrophages - metabolism; metabolism; MLX; MLXIP; MLXIPL; MondoA; MondoB; Protein Binding; Proteome - analysis; Proteome - metabolism; RNA, Small Interfering; transcription factor; Transcription, Genetic
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.01.014

Lipid droplets (LDs) store lipids for energy 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 macrophages, a cell type involved in metabolic diseases. Among ∼550 identified screen hits is MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates metabolic processes. We show that MLX and glucose-sensing family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs accumulate in cells, these transcription factors bind to LDs, reducing their availability for transcriptional activity and attenuating the response to glucose. Conversely, the absence of LDs results in hyperactivation of MLX target genes. Our findings uncover a paradigm for a lipid storage response in which binding of MLX transcription factors to LD surfaces adjusts the expression of metabolic genes to lipid storage levels. [Display omitted] •Global RNAi screening identifies determinants of lipid storage in human macrophages•RNAi screen hits belong to six major classes with distinct lipid droplet morphology•MLX family of transcription factors bind to lipid droplets via amphipathic helices•Lipid droplet binding reduces MLX/MLXIP/MLXIPL transcriptional activity Mejhert et al. identify genetic determinants of lipid storage in macrophages by integrating a global genome perturbation screen with lipid droplet proteomics. Among hits that localize to lipid droplets is the transcription factor MLX. By binding to lipid droplets, MLX coordinates lipid storage with metabolic gene expression regulation.