L-Serine deficiency elicits intracellular accumulation of cytotoxic deoxysphingolipids and lipid body formation

Kayoko Esaki, Tomoko Sayano, Chiaki Sonoda, Takumi Akagi, Takeshi Suzuki, Takuya Ogawa, Masahiro Okamoto, Takeo Yoshikawa, Yoshio Hirabayashi, Shigeki Furuya

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

L-Serine is required to synthesize membrane lipids such as phosphatidylserine and sphingolipids. Nevertheless, it remains largely unknownhowadiminishedcapacityto 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-deox-ysphingolipids (doxSLs), including 1-deoxysphinganine, in mouse embryonicfibroblasts(KO-MEFs)lackingD-3-phosphoglyceratede-hydrogenase (Phgdh), which catalyzes the first step in the de novo synthesis of L-serine. A novel mass spectrometry-based lipidomic approach demonstrated that 1-deoxydihydroceramide 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, whereas 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-al-anine 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, brainspecific 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 lackingPhgdh, andde novosynthesis of L-serineisnecessary to maintain normal sphingolipid homeostasis when the external supply of this amino acid is limited.

Original languageEnglish
Pages (from-to)14595-14609
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number23
DOIs
Publication statusPublished - Jun 5 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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