The cell nucleus is surrounded by a double membrane. The lipid packing and viscosity of membranes is critical for their function and is tightly controlled by lipid saturation. Circuits regulating the lipid saturation of the outer nuclear membrane (ONM) and contiguous endoplasmic reticulum (ER) are known. However, how lipid saturation is controlled in the inner nuclear membrane (INM) has remained enigmatic. Using INM biosensors and targeted genetic manipulations, we show that increased lipid unsaturation causes a reprogramming of lipid storage metabolism across the nuclear envelope (NE). Cells induce lipid droplet (LD) formation specifically from the distant ONM/ER, whereas LD formation at the INM is suppressed. In doing so, unsaturated fatty acids are shifted away from the INM. We identify the transcription circuits that topologically reprogram LD synthesis and identify seipin and phosphatidic acid as critical effectors. Our study suggests a detoxification mechanism protecting the INM from excess lipid unsaturation.

细胞核被双层膜包围。膜的脂质堆积和粘度对其功能至关重要，并受脂质饱和度的严格控制。调节外核膜 (ONM) 和连续内质网 (ER) 脂质饱和度的回路是已知的。然而，如何在内核膜 (INM) 中控制脂质饱和度仍然是个谜。使用 INM 生物传感器和有针对性的基因操作，我们表明增加的脂质不饱和度会导致跨核膜 (NE) 的脂质储存代谢重新编程。细胞特异性地从远处的 ONM/ER 诱导脂滴 (LD) 形成，而 INM 的 LD 形成受到抑制。在这样做时，不饱和脂肪酸从 INM 转移。我们确定了拓扑重编程LD合成的转录回路，并将seipin和磷脂酸确定为关键效应物。我们的研究表明有一种解毒机制可以保护 INM 免受过度的脂质不饱和。