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

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.

Sweet Sixteenth for ChREBP: Established Roles and Future Goals.

With the identification of ChREBP in 2001, our interest in understanding the molecular control of carbohydrate sensing has surged. While ChREBP was initially studied as a master regulator of lipogenesis in liver and fat tissue, it is now clear that ChREBP functions as a central metabolic coordinator in a variety of cell types in response to environmental and hormonal signals, with wide implications in health and disease. Celebrating its sweet sixteenth birthday, we review here the current knowledge about the function and regulation of ChREBP throughout usual and less explored tissues, to recapitulate ChREBP's role as a whole-body glucose sensor.