Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio, United States of America.
PLoS One. 2012;7(6):e39787. doi: 10.1371/journal.pone.0039787. Epub 2012 Jun 22.
Recent studies have demonstrated that human stearoylCoA desaturase-1 (SCD1), a Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids, controls the rate of lipogenesis, cell proliferation and tumorigenic capacity in cancer cells. However, the biological function of stearoylCoA desaturase-5 (SCD5), a second isoform of human SCD that is highly expressed in brain, as well as its potential role in human disease, remains unknown. In this study we report that the constitutive overexpression of human SCD5 in mouse Neuro2a cells, a widely used cell model of neuronal growth and differentiation, displayed a greater n-7 MUFA-to-SFA ratio in cell lipids compared to empty-vector transfected cells (controls). De novo synthesis of phosphatidylcholine and cholesterolesters was increased whereas phosphatidylethanolamine and triacylglycerol formation was reduced in SCD5-expressing cells with respect to their controls, suggesting a differential use of SCD5 products for lipogenic reactions. We also observed that SCD5 expression markedly accelerated the rate of cell proliferation and suppressed the induction of neurite outgrowth, a typical marker of neuronal differentiation, by retinoic acid indicating that the desaturase plays a key role in the mechanisms of cell division and differentiation. Critical signal transduction pathways that are known to modulate these processes, such epidermal growth factor receptor (EGFR)Akt/ERK and Wnt, were affected by SCD5 expression. Epidermal growth factor-induced phosphorylation of EGFR, Akt and ERK was markedly blunted in SCD5-expressing cells. Furthermore, the activity of canonical Wnt was reduced whereas the non-canonical Wnt was increased by the presence of SCD5 activity. Finally, SCD5 expression increased the secretion of recombinant Wnt5a, a non-canonical Wnt, whereas it reduced the cellular and secreted levels of canonical Wnt7b. Our data suggest that, by a coordinated modulation of key lipogenic pathways and transduction signaling cascades, SCD5 participates in the regulation of neuronal cell growth and differentiation.
最近的研究表明，人类硬脂酰辅酶 A 去饱和酶-1（SCD1）是一种 Δ9 去饱和酶，可将饱和脂肪酸（SFA）转化为单不饱和脂肪酸，控制癌细胞的脂肪生成、细胞增殖和致瘤能力。然而，高度表达于大脑的人类 SCD 的第二种同工酶硬脂酰辅酶 A 去饱和酶-5（SCD5）的生物学功能及其在人类疾病中的潜在作用尚不清楚。在这项研究中，我们报告了在广泛用于神经元生长和分化的细胞模型 Neuro2a 小鼠中，组成型过表达人 SCD5 与空载体转染细胞（对照）相比，细胞脂质中的 n-7 MUFA 与 SFA 的比例更高。与对照相比，SCD5 表达细胞中新合成的磷脂酰胆碱和胆固醇酯增加，而磷脂酰乙醇胺和三酰基甘油的形成减少，表明 SCD5 产物用于脂生成反应的差异。我们还观察到，SCD5 表达显著加速细胞增殖速度，并抑制维甲酸诱导的神经突生长，这是神经元分化的典型标志，表明该去饱和酶在细胞分裂和分化的机制中起着关键作用。已知调节这些过程的关键信号转导途径，如表皮生长因子受体（EGFR）Akt/ERK 和 Wnt，受到 SCD5 表达的影响。表皮生长因子诱导的 EGFR、Akt 和 ERK 磷酸化在 SCD5 表达细胞中明显减弱。此外，存在 SCD5 活性会降低经典 Wnt 的活性，而增加非经典 Wnt 的活性。最后，SCD5 表达增加了重组非经典 Wnt5a 的分泌，而降低了经典 Wnt7b 的细胞内和分泌水平。我们的数据表明，通过对关键脂生成途径和转导信号级联的协调调节，SCD5 参与了神经元细胞生长和分化的调节。
