期刊
CANCER & METABOLISM
卷 8, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40170-020-00212-x
关键词
PHGDH; Serine; Ceramide; Triacylglycerol; Mouse model
资金
- NIH [K22-CA197058, R03-CA227349, R37-CA230042]
- PanCAN/AACR Pathway to Leadership Award [14-70-25-DENI]
- AACR-Takeda Oncology Lung Cancer Research Fellowship
- NCI [P30-CA076292]
- Moffitt Foundation
- Florida Bankhead-Coley grant [06BS-02-9614]
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.
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