Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Institute of Plant and Microbial Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
Development. 2020 Oct 16;147(20):dev192997. doi: 10.1242/dev.192997.
Seipin, an evolutionary conserved protein, plays pivotal roles during lipid droplet (LD) biogenesis and is associated with various human diseases with unclear mechanisms. Here, we analyzed mutants deleted of the sole gene, Homozygous mutants displayed penetrant embryonic lethality, which is caused by the disruption of the lipid-rich permeability barrier, the innermost layer of the embryonic eggshell. In oocytes and embryos, SEIP-1 is associated with LDs and is crucial for controlling LD size and lipid homeostasis. The deletion mutants reduced the ratio of polyunsaturated fatty acids (PUFAs) in their embryonic fatty acid pool. Interestingly, dietary supplementation of selected n-6 PUFAs rescued the embryonic lethality and defective permeability barrier. Accordingly, we propose that SEIP-1 may maternally regulate LD biogenesis and lipid homeostasis to orchestrate the formation of the permeability barrier for eggshell synthesis during embryogenesis. A lipodystrophy allele of resulted in embryonic lethality as well and could be rescued by PUFA supplementation. These experiments support a great potential for using to model SEIPIN-associated human diseases.
Seipin 是一种进化上保守的蛋白质，在脂滴 (LD) 的生物发生中发挥关键作用，与多种人类疾病有关，但机制尚不清楚。在这里，我们分析了唯一基因缺失的 突变体，纯合 突变体表现出明显的胚胎致死性，这是由于富含脂质的通透性屏障（胚胎蛋壳的最内层）被破坏所致。在卵母细胞和胚胎中，SEIP-1 与 LD 相关，对于控制 LD 大小和脂质平衡至关重要。 缺失突变体降低了其胚胎脂肪酸库中多不饱和脂肪酸 (PUFA) 的比例。有趣的是，选择的 n-6 PUFAs 的饮食补充挽救了胚胎致死性和有缺陷的通透性屏障。因此，我们提出 SEIP-1 可能通过母体调节 LD 的生物发生和脂质平衡来协调胚胎发生期间蛋壳合成的通透性屏障的形成。结果表明， 脂肪营养不良等位基因也导致胚胎致死，并且可以通过 PUFA 补充来挽救。这些实验支持利用 来模拟 SEIPIN 相关人类疾病的巨大潜力。
