Background d -3-phosphoglycerate dehydrogenase (PHGDH), which encodes the first enzyme in serine biosynthesis, is overexpressed in human cancers and has been proposed as a drug target. However, whether PHGDH is critical for the proliferation or homeostasis of tissues following the postnatal period is unknown. Methods To study PHGDH inhibition in adult animals, we developed a knock-in mouse model harboring a PHGDH shRNA under the control of a doxycycline-inducible promoter. With this model, PHGDH depletion can be globally induced in adult animals, while sparing the brain due to poor doxycycline delivery. Results We found that PHGDH depletion is well tolerated, and no overt phenotypes were observed in multiple highly proliferative cell compartments. Further, despite detectable knockdown and impaired serine synthesis, liver and pancreatic functions were normal. Interestingly, diminished PHGDH expression reduced liver serine and ceramide levels without increasing the levels of deoxysphingolipids. Further, liver triacylglycerol profiles were altered, with an accumulation of longer chain, polyunsaturated tails upon PHGDH knockdown. Conclusions These results suggest that dietary serine is adequate to support the function of healthy, adult murine tissues, but PHGDH-derived serine supports liver ceramide synthesis and sustains general lipid homeostasis.

中文翻译：

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PHGDH 支持肝脏神经酰胺合成并维持脂质稳态

背景 d -3-磷酸甘油酸脱氢酶 (PHGDH) 编码丝氨酸生物合成中的第一种酶，在人类癌症中过度表达，并已被提议作为药物靶点。然而，PHGDH 是否对产后组织的增殖或稳态至关重要尚不清楚。方法 为了研究成年动物对 PHGDH 的抑制作用，我们开发了一种敲入小鼠模型，该模型含有受强力霉素诱导型启动子控制的 PHGDH shRNA。使用该模型，可以在成年动物中全局诱导 PHGDH 消耗，同时由于强力霉素递送不良而保留大脑。结果我们发现 PHGDH 消耗具有良好的耐受性，并且在多个高度增殖的细胞隔室中没有观察到明显的表型。此外，尽管可检测到敲低和丝氨酸合成受损，肝、胰功能正常。有趣的是，减少的 PHGDH 表达降低了肝脏丝氨酸和神经酰胺的水平，而没有增加脱氧鞘脂的水平。此外，肝脏甘油三酯谱发生了改变，在 PHGDH 敲低时会积累更长的链、多不饱和尾巴。结论 这些结果表明，膳食丝氨酸足以支持健康的成年鼠组织的功能，但 PHGDH 衍生的丝氨酸支持肝脏神经酰胺的合成并维持一般的脂质稳态。