Li Qi, Zhou Xiaofang, Zhang Xiaocong, Zhang Chuqi, Zhang Shaobing O
Laboratory of Metabolic Genetics, College of Life Sciences, Capital Normal University, Beijing, China.
Nat Commun. 2025 Apr 27;16(1):3955. doi: 10.1038/s41467-025-59256-6.
Lipid droplet (LD) fusion plays a key role in cellular fat storage. How the phospholipid monolayer membrane of LD functions in fusion, however, is poorly understood. In Caenorhabditis elegans, loss of cytochrome P450 protein CYP-37A1 causes de-repression of nuclear receptor DAF-12, promoting thermosensitive LD fusion. Here, we report that in cyp-37A1 mutants, DAF-12 up-regulates the transcription and LD localization of seven fatty acid desaturases (FAT-1 to FAT-7) and a lysophosphatidylcholine acyltransferase 3 (LPCAT3) homolog MBOA-6. LD-targeting of these enzymes increases phosphatidylcholine (PC) containing ω-3 C20 polyunsaturated fatty acids, which are essential for thermosensitive fusion. ω-3 C20-PC increase LD membrane fluidity, as does high ambient temperature. Lowering LD membrane fluidity by a chemical membrane rigidifier attenuates thermosensitive fusion; ectopic targeting of ω3 desaturase FAT-1 or MBOA-6 to LDs increases fusion kinetics and thermosensitivity. Furthermore, human LPCAT3 localizes to LDs, positively regulates LD size in human cells and facilitates thermosensitive fusion in C. elegans. These results demonstrate that DAF-12 signaling regulates compartmentalized membrane remodeling and fluidization to facilitate conserved thermosensitive LD fusion.
脂滴融合在细胞脂肪储存中起关键作用。然而，脂滴的磷脂单分子层膜在融合过程中的功能却鲜为人知。在秀丽隐杆线虫中，细胞色素P450蛋白CYP - 37A1的缺失导致核受体DAF - 12的去抑制，从而促进热敏性脂滴融合。在此，我们报道在cyp - 37A1突变体中，DAF - 12上调了七种脂肪酸去饱和酶（FAT - 1至FAT - 7）和溶血磷脂酰胆碱酰基转移酶3（LPCAT3）同源物MBOA - 6的转录及脂滴定位。这些酶靶向脂滴会增加含有ω-3 C20多不饱和脂肪酸的磷脂酰胆碱（PC），而这些脂肪酸对于热敏性融合至关重要。ω-3 C20 - PC会增加脂滴膜的流动性，高温也会如此。用化学膜硬化剂降低脂滴膜的流动性会减弱热敏性融合；将ω3去饱和酶FAT - 1或MBOA - 6异位靶向脂滴会增加融合动力学和热敏性。此外，人类LPCAT3定位于脂滴，在人类细胞中正向调节脂滴大小，并促进秀丽隐杆线虫中的热敏性融合。这些结果表明，DAF - 12信号通路调节分隔的膜重塑和流化，以促进保守的热敏性脂滴融合。
