Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cell Biology, Yale School of Medicine, New Haven, CT 06510, USA.
Mol Cell. 2020 Mar 19;77(6):1251-1264.e9. doi: 10.1016/j.molcel.2020.01.014. Epub 2020 Feb 4.
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.
脂滴（LDs）储存脂质以供能量，并且是细胞脂质动态平衡的核心。协调 LDs 中的脂质储存与细胞代谢的机制尚不清楚，但与肥胖相关疾病有关。在这里，我们利用全基因组筛选来鉴定调节巨噬细胞中脂质储存的基因，巨噬细胞是一种与代谢疾病有关的细胞类型。在约 550 个鉴定出的筛选命中中，有一个是 MLX，它是一种调节代谢过程的基本螺旋-环-螺旋亮氨酸拉链转录因子。我们表明，MLX 以及葡萄糖感应家族成员 MLXIP/MondoA 和 MLXIPL/ChREBP 通过 C 末端两亲性螺旋结合到 LD 上。当细胞中 LD 积累时，这些转录因子结合到 LD 上，降低其转录活性的可用性，并减弱对葡萄糖的反应。相反，LD 的缺失导致 MLX 靶基因的过度激活。我们的发现揭示了一种脂质储存反应的范例，其中 MLX 转录因子与 LD 表面的结合根据脂质储存水平调整代谢基因的表达。
