Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 23, Pages 14595-14609Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.603860
Keywords
-
Categories
Funding
- Tojuro Iijima Foundation for Food and Technology
- Japan Society for the Promotion of Science KAKENHI [14J05809]
- Junior Research Associate of RIKEN
- Grants-in-Aid for Scientific Research [15K19754, 24614007, 14J05809] Funding Source: KAKEN
Ask authors/readers for more resources
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 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-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available