Inositol is an essential metabolite that serves as a precursor for structural and signaling molecules. Although perturbation of inositol homeostasis has been implicated in numerous human disorders, surprisingly little is known about how inositol levels are regulated in mammalian cells. A recent study in mouse embryonic fibroblasts (MEFs) demonstrated that nuclear translocation of inositol hexakisphosphate kinase 1 (IP6K1) mediates repression of myo-inositol-3-P synthase (MIPS), the rate-limiting inositol biosynthetic enzyme. Binding of IP6K1 to phosphatidic acid (PA) is required for this repression. Here, we elucidate the role of PA in IP6K1 repression. Our results indicate that increasing PA levels through pharmacological stimulation of phospholipase D (PLD) or direct supplementation of 18:1 PA induces nuclear translocation of IP6K1 and represses expression of the MIPS protein. We found that this effect was specific to PA synthesized in the plasma membrane, as ER-derived PA did not induce IP6K1 translocation. Furthermore, we determined that PLD-mediated PA synthesis can be stimulated by the master metabolic regulator 5' AMP-activated protein kinase (AMPK). We show that activation of AMPK by glucose deprivation or by treatment with the mood-stabilizing drugs valproate (VPA) or lithium recapitulated IP6K1 nuclear translocation and decreased MIPS expression. This study demonstrates for the first time that modulation of PA levels through the AMPK-PLD pathway regulates IP6K1-mediated repression of MIPS.

肌醇是一种重要的代谢物，可作为结构分子和信号分子的前体。尽管肌醇稳态的扰动与许多人类疾病有关，但令人惊讶的是，关于肌醇水平如何在哺乳动物细胞中被调节知之甚少。最近对小鼠胚胎成纤维细胞 (MEF) 的一项研究表明，肌醇六磷酸激酶 1 (IP6K1) 的核转位介导了肌醇的抑制。肌醇-3-P合酶（MIPS），一种限速肌醇生物合成酶。这种抑制需要 IP6K1 与磷脂酸 (PA) 结合。在这里，我们阐明了 PA 在 IP6K1 抑制中的作用。我们的结果表明，通过药理学刺激磷脂酶 D (PLD) 或直接补充 18:1 PA 来增加 PA 水平会诱导 IP6K1 的核转位并抑制 MIPS 蛋白的表达。我们发现这种效应对质膜中合成的 PA 具有特异性，因为 ER 衍生的 PA 不会诱导 IP6K1 易位。此外，我们确定 PLD 介导的 PA 合成可以受到主要代谢调节剂 5' AMP 活化蛋白激酶 (AMPK) 的刺激。我们表明，通过剥夺葡萄糖或通过用稳定情绪的药物丙戊酸盐 (VPA) 或锂治疗来激活 AMPK 可重现 IP6K1 核易位并降低 MIPS 表达。该研究首次证明通过 AMPK-PLD 途径调节 PA 水平可调节 IP6K1 介导的 MIPS 抑制。