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.

中文翻译：

---

MLX 家族转录因子分配至脂滴可调节代谢基因表达。

脂滴 (LD) 储存脂质以获取能量，对于细胞脂质稳态至关重要。LD 中脂质储存与细胞代谢的协调机制尚不清楚，但与肥胖相关疾病有关。在这里，我们利用全基因组筛选来识别调节巨噬细胞（一种与代谢疾病有关的细胞类型）中脂质储存的基因。在大约 550 个已识别的屏幕点击中，MLX 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。我们发现 MLX 和葡萄糖感应家族成员 MLXIP/MondoA 和 MLXIPL/ChREBP 通过 C 端两亲性螺旋结合 LD。当 LD 在细胞中积累时，这些转录因子会与 LD 结合，从而降低其转录活性的可用性并减弱对葡萄糖的反应。相反，LD 的缺失会导致 MLX 靶基因过度激活。我们的研究结果揭示了脂质储存反应的范例，其中 MLX 转录因子与 LD 表面的结合可调节代谢基因的表达以适应脂质储存水平。