PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

Abstract

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, liver and pancreatic function were normal. Interestingly, diminished PHGDH expression in the liver reduced 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.

Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition

“…In addition, humans with hypomorphic mutations in PHGDH exhibit developmental delays that can be ameliorated by serine supplementation, suggesting that transitory PHGDH inhibition following completion of neuronal development may be tolerable. Moreover, a recent study found that systemic depletion of PHGDH was well tolerated in multiple highly proliferative tissues in adult mice (76). These results suggest that PHGDH inhibitors may be well tolerated, provided that adequate serine and glycine are available in the diet.…”

Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

“…Among these tissues, the expression and activity of the phosphorylated pathway in the liver are regulated by systemic levels of protein/amino acid nutrition and hormones [ 7 , 8 ]. Recent studies have implicated that Phgdh-dependent Ser synthesis supports general lipid homeostasis [ 9 ] and appears to prevent non-alcoholic fatty liver disease [ 10 , 11 , 12 ]. Nonetheless, it remains unclear how de novo Ser synthesis via the phosphorylated pathway contributes to the physiological function of the liver at steady state.…”