L-Serine deficiency elicits intracellular accumulation of cytotoxic deoxy-sphingolipids and lipid body formation [Metabolism]

April 22nd, 2015 by Esaki, K., Sayano, T., Sonoda, C., Akagi, T., Suzuki, T., Ogawa, T., Okamoto, M., Yoshikawa, T., Hirabayashi, Y., Furuya, S.

L-Serine is required to synthesize membrane lipids such as phosphatidylserine and sphingolipids. Nevertheless, it remains largely unknown how a diminished capacity to synthesize L-serine affects lipid homeostasis in cells and tissues. Here, we show that deprivation of external L-serine leads to the generation of 1-deoxy-sphingolipids (doxSLs), including 1-deoxy-sphinganine, in mouse embryonic fibroblasts (KO-MEFs) lacking D-3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step in the de novo synthesis of L-serine. A novel mass spectrometry-based lipidomic approach demonstrated that 1-deoxy-dihydroceramide was the most abundant species of doxSLs accumulated in L-serine-deprived KO-MEFs. Among normal sphingolipid species in KO-MEFs, levels of sphinganine, dihydroceramide, ceramide, and hexosylceramide were significantly reduced after deprivation of external L-serine, while those of sphingomyelin, sphingosine, and sphingosine-1-phosphate were retained. The synthesis of doxSLs was suppressed by supplementing the culture medium with L-serine, but was potentiated by increasing the ratio of L-alanine to L-serine in the medium. Unlike with L-serine, depriving cells of external L-leucine did not promote the occurrence of doxSLs. Consistent with results obtained from KO-MEFs, brain-specific deletion of Phgdh in mice also resulted in accumulation of doxSLs in the brain. Furthermore, L-serine-deprived KO-MEFs exhibited increased formation of cytosolic lipid bodies containing doxSLs and other sphingolipids. These in vitro and in vivo studies indicate that doxSLs are generated in the presence of a high ratio of L-alanine to L-serine in cells and tissues lacking Phgdh, and de novo synthesis of L-serine is necessary to maintain normal sphingolipid homeostasis when the external supply of this amino acid is limited.