Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (Lipin^ΔNLS ), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic, but not the nuclear gene regulatory activity of Lipin, is essential for survival. Notably, adult Lipin^ΔNLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were mis-regulated in Lipin^ΔNLS flies. Combined, our data suggest that nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

中文翻译：

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脂质的核转位能力对进食和禁食果蝇的基因表达和存活有不同的影响。


脂质是真核蛋白质，具有脂质合成和能量平衡稳态控制的功能。它们通过在细胞质中充当磷脂酸磷酸酶并通过易位到细胞核后改变基因表达来执行这些功能，特别是在禁食条件下。在这里，我们询问果蝇脂质的核易位和酶活性是否发挥重要功能，以及当核易位受损时，在进食和禁食条件下基因表达如何变化。为了解决这些问题，我们创建了一个Lipin无效突变体、一个表达缺乏核定位信号的 Lipin 的突变体 ( Lipin ^ΔNLS )，以及一个表达酶促死亡的 Lipin 的突变体。我们的数据支持这样的结论：脂质的酶活性而非核基因调控活性对于生存至关重要。值得注意的是，成年Lipin ^ΔNLS果蝇不仅能存活，而且预期寿命也有所提高。相比之下，他们非常容易挨饿。进食状态下预期寿命的延长和禁食状态下生存率的降低都与代谢基因表达的变化相关。此外，喂食的果蝇预期寿命的增加与代谢率的降低有关。有趣的是，除了代谢基因外，与摄食行为和免疫反应有关的基因在Lipin ^ΔNLS果蝇中也被错误调节。综合起来，我们的数据表明，脂质的核活性影响基因组对营养物质可用性的反应，从而影响预期寿命和饥饿抵抗力。 因此，旨在降低人类脂质核易位的营养或治疗方法可能值得探索。