title: L-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation.
abstract: 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-deoxysphingolipids (doxSLs), including 1-deoxysphinganine, 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-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-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.
authors.affiliation: From the Laboratories of Functional Genomics and Metabolism and the Laboratories for Molecular Psychiatry and Molecular Membrane Neuroscience.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Esaki
authors.affiliation: From the Laboratories of Functional Genomics and Metabolism and Molecular Membrane Neuroscience.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sayano
authors.affiliation: From the Laboratories of Functional Genomics and Metabolism and.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Sonoda
authors.affiliation: Support Unit for Neuromorphological Analysis, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, and.
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.affiliation: Synthetic Biology, Division of Systems Bioengineering, Graduate School of Bioresource and Bioenvironmental Sciences, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: the Department of Pharmaceutical Sciences, International University of Health and Welfare, Tochigi 324-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Synthetic Biology, Division of Systems Bioengineering, Graduate School of Bioresource and Bioenvironmental Sciences, and Bio-Architecture Center, Kyushu University, Fukuoka 812-8581.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: the Laboratories for Molecular Psychiatry and.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Molecular Membrane Neuroscience.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
authors.affiliation: From the Laboratories of Functional Genomics and Metabolism and Bio-Architecture Center, Kyushu University, Fukuoka 812-8581, shigekifur@brs.kyushu-u.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Furuya
mesh_terms: D000409:Alanine / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D055786:Gene Knockout Techniques; D066292:Lipid Droplets / Q000378:metabolism*; D008055:Lipids; D051379:Mice; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000172:deficiency / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008055:Lipids; D013107:Sphingolipids; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D013110:Sphingosine; D000409:Alanine; C408363:spisulosine
keywords: amino acid; inborn error of metabolism; mass spectrometry (MS); serine; sphingolipid