Abstract
One hundred and fifty years ago, Johann Thudichum described sphingolipids as unusual “Sphinx-like” lipids from the brain. Today, we know that thousands of sphingolipid molecules mediate many essential functions in embryonic development and normal physiology. In addition, sphingolipid metabolism and signalling pathways are dysregulated in a wide range of pathologies, and therapeutic agents that target sphingolipids are now used to treat several human diseases. However, our understanding of sphingolipid regulation at cellular and organismal levels and their functions in developmental, physiological and pathological settings is rudimentary. In this Review, we discuss recent advances in sphingolipid pathways in different organelles, how secreted sphingolipid mediators modulate physiology and disease, progress in sphingolipid-targeted therapeutic and diagnostic research, and the trans-cellular sphingolipid metabolic networks between microbiota and mammals. Advances in sphingolipid biology have led to a deeper understanding of mammalian physiology and may lead to progress in the management of many diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Thudichum, J. L. W. A Treatise on the Chemical Constitution of the Brain (Archon Books, 1962).
Carter, H. E. & Humiston, C. G. Biochemistry of the sphingolipides. V. The structure of sphingine. J. Biol. Chem. 191, 727–733 (1951).
Klenk, E. Contribution to the concept of gangliosides [German]. Hoppe Seylers Z. Physiol. Chem. 288, 216–220 (1951).
Brady, R. O. The sphingolipidoses. N. Engl. J. Med. 275, 312–318 (1966).
Stoffel, W. Sphingolipids. Annu. Rev. Biochem. 40, 57–82 (1971).
Hannun, Y. A. & Bell, R. M. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235, 670–674 (1987).
Kolesnick, R. N. 1,2-Diacylglycerols but not phorbol esters stimulate sphingomyelin hydrolysis in GH3 pituitary cells. J. Biol. Chem. 262, 16759–16762 (1987).
Obeid, L. M., Linardic, C. M., Karolak, L. A. & Hannun, Y. A. Programmed cell death induced by ceramide. Science 259, 1769–1771 (1993).
Ghosh, T. K., Bian, J. & Gill, D. L. Intracellular calcium release mediated by sphingosine derivatives generated in cells. Science 248, 1653–1656 (1990).
Olivera, A. & Spiegel, S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365, 557–560 (1993).
Choi, O. H., Kim, J. H. & Kinet, J. P. Calcium mobilization via sphingosine kinase in signalling by the Fc epsilon RI antigen receptor. Nature 380, 634–636 (1996).
Hla, T. & Maciag, T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J. Biol. Chem. 265, 9308–9313 (1990).
Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552–1555 (1998).
Hla, T., Lee, M. J., Ancellin, N., Paik, J. H. & Kluk, M. J. Lysophospholipids–receptor revelations. Science 294, 1875–1878 (2001).
Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010).
Hojjati, M. R., Li, Z. & Jiang, X. C. Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochim. Biophys. Acta 1737, 44–51 (2005).
Buede, R., Rinker-Schaffer, C., Pinto, W. J., Lester, R. L. & Dickson, R. C. Cloning and characterization of LCB1, a Saccharomyces gene required for biosynthesis of the long-chain base component of sphingolipids. J. Bacteriol. 173, 4325–4332 (1991).
Park, W. J. & Park, J. W. The role of sphingolipids in endoplasmic reticulum stress. FEBS Lett. 594, 3632–3651 (2020).
Hernandez-Corbacho, M. J., Salama, M. F., Canals, D., Senkal, C. E. & Obeid, L. M. Sphingolipids in mitochondria. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862, 56–68 (2017).
Dunn, T. M., Tifft, C. J. & Proia, R. L. A perilous path: the inborn errors of sphingolipid metabolism. J. Lipid Res. 60, 475–483 (2019).
Mandon, E. C., Ehses, I., Rother, J., van Echten, G. & Sandhoff, K. Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver. J. Biol. Chem. 267, 11144–11148 (1992).
Brady, R. O. & Koval, G. J. The enzymatic synthesis of sphingosine. J. Biol. Chem. 233, 26–31 (1958).
Brady, R. O., Formica, J. V. & Koval, G. J. The enzymatic synthesis of sphingosine. II. Further studies on the mechanism of the reaction. J. Biol. Chem. 233, 1072–1076 (1958).
Weiss, B. & Stoffel, W. Human and murine serine-palmitoyl-CoA transferase — cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur. J. Biochem. 249, 239–247 (1997).
Hornemann, T., Richard, S., Rutti, M. F., Wei, Y. & von Eckardstein, A. Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. J. Biol. Chem. 281, 37275–37281 (2006).
Han, G. et al. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc. Natl Acad. Sci. USA 106, 8186–8191 (2009).
Mandon, E. C., van Echten, G., Birk, R., Schmidt, R. R. & Sandhoff, K. Sphingolipid biosynthesis in cultured neurons. Down-regulation of serine palmitoyltransferase by sphingoid bases. Eur. J. Biochem. 198, 667–674 (1991).
Davis, D. L., Gable, K., Suemitsu, J., Dunn, T. M. & Wattenberg, B. W. The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: reconstitution of SPT regulation in isolated membranes. J. Biol. Chem. 294, 5146–5156 (2019).
Breslow, D. K. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 463, 1048–1053 (2010).
Mohassel, P. et al. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat. Med. 27, 1197–1204 (2021).
Srivastava, S. et al. SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Brain 146, 1420–1435 (2023).
Lone, M. A. et al. SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. J. Clin. Invest. 132, e161908 (2022).
Beeler, T. et al. The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Δ mutant. J. Biol. Chem. 273, 30688–30694 (1998).
Kihara, A. & Igarashi, Y. FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. J. Biol. Chem. 279, 49243–49250 (2004).
Liu, Q. et al. 3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia. Leukemia 36, 100–110 (2022).
Pilz, R. et al. Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients. Hum. Mol. Genet. 31, 1105–1114 (2022).
Guillas, I. et al. C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. EMBO J. 20, 2655–2665 (2001).
Schorling, S., Vallee, B., Barz, W. P., Riezman, H. & Oesterhelt, D. Lag1p and Lac1p are essential for the Acyl-CoA-dependent ceramide synthase reaction in Saccharomyces cerevisae. Mol. Biol. Cell 12, 3417–3427 (2001).
Levy, M. & Futerman, A. H. Mammalian ceramide synthases. IUBMB Life 62, 347–356 (2010).
Zelnik, I. D., Rozman, B., Rosenfeld-Gur, E., Ben-Dor, S. & Futerman, A. H. A stroll down the CerS lane. Adv. Exp. Med. Biol. 1159, 49–63 (2019).
York, A. G. et al. IL-10 constrains sphingolipid metabolism to limit inflammation. Nature 627, 628–635 (2024).
Griess, K. et al. Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat. Cell Biol. 25, 20–29 (2023).
Siddique, M. M., Li, Y., Chaurasia, B., Kaddai, V. A. & Summers, S. A. Dihydroceramides: from bit players to lead actors. J. Biol. Chem. 290, 15371–15379 (2015).
Chaurasia, B. et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science 365, 386–392 (2019).
Hammerschmidt, P. et al. CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity. Cell 177, 1536–1552.e23 (2019).
Senkal, C. E. et al. Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J. Biol. Chem. 286, 42446–42458 (2011).
van der Bijl, P., Strous, G. J., Lopes-Cardozo, M., Thomas-Oates, J. & van Meer, G. Synthesis of non-hydroxy-galactosylceramides and galactosyldiglycerides by hydroxy-ceramide galactosyltransferase. Biochem. J. 317, 589–597 (1996).
Takahashi, T. & Suzuki, T. Role of sulfatide in normal and pathological cells and tissues. J. Lipid Res. 53, 1437–1450 (2012).
Venkataraman, K. & Futerman, A. H. Do longevity assurance genes containing Hox domains regulate cell development via ceramide synthesis? FEBS Lett. 528, 3–4 (2002).
Sociale, M. et al. Ceramide synthase schlank is a transcriptional regulator adapting gene expression to energy requirements. Cell Rep. 22, 967–978 (2018).
Mendelson, K. et al. The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis. eLife 6, e21992 (2017).
Mandala, S. M. et al. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death. Proc. Natl Acad. Sci. USA 97, 7859–7864 (2000).
Ogawa, C., Kihara, A., Gokoh, M. & Igarashi, Y. Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2. J. Biol. Chem. 278, 1268–1272 (2003).
Van Veldhoven, P. P. & Mannaerts, G. P. Subcellular localization and membrane topology of sphingosine-1-phosphate lyase in rat liver. J. Biol. Chem. 266, 12502–12507 (1991).
Saba, J. D., Nara, F., Bielawska, A., Garrett, S. & Hannun, Y. A. The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase. J. Biol. Chem. 272, 26087–26090 (1997).
Ikeda, M., Kihara, A. & Igarashi, Y. Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5’-phosphate binding domain exposed to the cytosol. Biochem. Biophys. Res. Commun. 325, 338–343 (2004).
Bektas, M. et al. Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver. J. Biol. Chem. 285, 10880–10889 (2010).
Arana, L., Gangoiti, P., Ouro, A., Trueba, M. & Gomez-Munoz, A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis. 9, 15 (2010).
Hoeferlin, L. A., Wijesinghe, D. S. & Chalfant, C. E. The role of ceramide-1-phosphate in biological functions. Handb. Exp. Pharmacol. 215, 153–166 (2013).
Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003).
Huitema, K., van den Dikkenberg, J., Brouwers, J. F. & Holthuis, J. C. Identification of a family of animal sphingomyelin synthases. EMBO J. 23, 33–44 (2004).
D’Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007).
Chatterjee, S., Ghosh, N. & Khurana, S. Purification of uridine diphosphate-galactose:glucosyl ceramide, β1-4 galactosyltransferase from human kidney. J. Biol. Chem. 267, 7148–7153 (1992).
Kawano, M., Kumagai, K., Nishijima, M. & Hanada, K. Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT. J. Biol. Chem. 281, 30279–30288 (2006)
Sugiki, T. et al. Structural basis for the Golgi association by the pleckstrin homology domain of the ceramide trafficking protein (CERT). J. Biol. Chem. 287, 33706–33718 (2012).
Villani, M. et al. Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. Biochem. J. 414, 31–41 (2008).
Fugmann, T. et al. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein. J. Cell Biol. 178, 15–22 (2007).
Kumagai, K. et al. Interorganelle trafficking of ceramide is regulated by phosphorylation-dependent cooperativity between the PH and START domains of CERT. J. Biol. Chem. 282, 17758–17766 (2007).
D’Angelo, G., Vicinanza, M., Di Campli, A. & De Matteis, M. A. The multiple roles of PtdIns(4)P – not just the precursor of PtdIns(4,5)P2. J. Cell Sci. 121, 955–963 (2008).
Mesmin, B. et al. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155, 830–843 (2013).
Mesmin, B. et al. Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP. EMBO J. 36, 3156–3174 (2017).
Capasso, S. et al. Sphingolipid metabolic flow controls phosphoinositide turnover at the trans-Golgi network. EMBO J. 36, 1736–1754 (2017).
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).
Lelieveld, S. H. et al. Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes. Am. J. Hum. Genet. 101, 478–484 (2017).
Gehin, C. et al. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis. J. Clin. Invest. 133, e165019 (2023).
Murakami, H. et al. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT. PLoS One 15, e0243980 (2020).
Crivelli, S. M. et al. CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer’s disease. Alzheimers Res. Ther. 13, 45 (2021).
Gewaid, H. et al. Sphingomyelin is essential for the structure and function of the double-membrane vesicles in hepatitis C virus RNA replication factories. J. Virol. 94, e01080–e01120 (2020).
Tachida, Y. et al. Chlamydia trachomatis-infected human cells convert ceramide to sphingomyelin without sphingomyelin synthases 1 and 2. FEBS Lett. 594, 519–529 (2020).
Carreira, A. C. et al. Mammalian sphingoid bases: biophysical, physiological and pathological properties. Prog. Lipid Res. 594, 100995 (2019).
Duran, J. M. et al. Sphingomyelin organization is required for vesicle biogenesis at the Golgi complex. EMBO J. 31, 4535–4546 (2012).
van Galen, J. et al. Sphingomyelin homeostasis is required to form functional enzymatic domains at the trans-Golgi network. J. Cell Biol. 206, 609–618 (2014).
Campelo, F. et al. Sphingomyelin metabolism controls the shape and function of the Golgi cisternae. eLife 6, e24603 (2017).
Sokoya, T. et al. Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway. eLife 11, e79278 (2022).
Pekkinen, M. et al. Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. JCI Insight 4, e126180 (2019).
Lipsky, N. G. & Pagano, R. E. Intracellular translocation of fluorescent sphingolipids in cultured fibroblasts: endogenously synthesized sphingomyelin and glucocerebroside analogues pass through the Golgi apparatus en route to the plasma membrane. J. Cell Biol. 100, 27–34 (1985).
Milhas, D., Clarke, C. J. & Hannun, Y. A. Sphingomyelin metabolism at the plasma membrane: implications for bioactive sphingolipids. FEBS Lett. 584, 1887–1894 (2010).
Ray, T. K., Skipski, V. P., Barclay, M., Essner, E. & Archibald, F. M. Lipid composition of rat liver plasma membranes. J. Biol. Chem. 244, 5528–5536 (1969).
Carreira, A. C., Ventura, A. E., Varela, A. R. & Silva, L. C. Tackling the biophysical properties of sphingolipids to decipher their biological roles. Biol. Chem. 396, 597–609 (2015).
Abe, M. et al. PMP2/FABP8 induces PI(4,5)P(2)-dependent transbilayer reorganization of sphingomyelin in the plasma membrane. Cell Rep. 37, 109935 (2021).
Alvarez-Prats, A. et al. Schwann-cell-specific deletion of phosphatidylinositol 4-kinase alpha causes aberrant myelination. Cell Rep. 23, 2881–2890 (2018).
Das, A., Brown, M. S., Anderson, D. D., Goldstein, J. L. & Radhakrishnan, A. Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. eLife 3, e02882 (2014).
Johnson, K. A., Endapally, S., Vazquez, D. C., Infante, R. E. & Radhakrishnan, A. Ostreolysin A and anthrolysin O use different mechanisms to control movement of cholesterol from the plasma membrane to the endoplasmic reticulum. J. Biol. Chem. 294, 17289–17300 (2019).
Endapally, S. et al. Molecular discrimination between two conformations of sphingomyelin in plasma membranes. Cell 176, 1040–1053.e17 (2019).
Scheek, S., Brown, M. S. & Goldstein, J. L. Sphingomyelin depletion in cultured cells blocks proteolysis of sterol regulatory element binding proteins at site 1. Proc. Natl Acad. Sci. USA 94, 11179–11183 (1997).
Kim, Y., Mavodza, G., Senkal, C. E. & Burd, C. G. Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis. J. Cell. Biol. 222, e202308055 (2023).
Bieberich, E. Sphingolipids and lipid rafts: novel concepts and methods of analysis. Chem. Phys. Lipids 216, 114–131 (2018).
Grassi, S. et al. Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases. J. Lipid Res. 61, 636–654 (2020).
Andreone, B. J. et al. Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron 94, 581–594.e5 (2017).
Russo, D., Parashuraman, S. & D’Angelo, G. Glycosphingolipid-protein interaction in signal transduction. Int. J. Mol. Sci. 17, 1732 (2016).
Malchiodi-Albedi, F. et al. Lipid raft disruption protects mature neurons against amyloid oligomer toxicity. Biochim. Biophys. Acta 1802, 406–415 (2010).
Pernber, Z., Blennow, K., Bogdanovic, N., Mansson, J. E. & Blomqvist, M. Altered distribution of the gangliosides GM1 and GM2 in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 33, 174–188 (2012).
Andersson, L. et al. Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking. Eur. Heart J. 42, 4481–4492 (2021).
Jongsma, M. L. M. et al. The SPPL3-defined glycosphingolipid repertoire orchestrates HLA class I-mediated immune responses. Immunity 54, 132–150.e9 (2021).
Capolupo, L. et al. Sphingolipids control dermal fibroblast heterogeneity. Science 376, eabh1623 (2022).
Quintern, L. E. et al. Acid sphingomyelinase from human urine: purification and characterization. Biochim. Biophys. Acta 922, 323–336 (1987).
Furst, W., Machleidt, W. & Sandhoff, K. The precursor of sulfatide activator protein is processed to three different proteins. Biol. Chem. Hoppe Seyler 369, 317–328 (1988).
O’Brien, J. S. et al. Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same genetic locus. Science 241, 1098–1101 (1988).
Kolter, T. & Sandhoff, K. Lysosomal degradation of membrane lipids. FEBS Lett. 584, 1700–1712 (2010).
Gatt, S. Enzymatic hydrolysis of sphingolipids. I. Hydrolysis and synthesis of ceramides by an enzyme from rat brain. J. Biol. Chem. 241, 3724–3730 (1966).
Sasaki, H., Arai, H., Cocco, M. J. & White, S. H. pH dependence of sphingosine aggregation. Biophys. J. 96, 2727–2733 (2009).
Lloyd-Evans, E. et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14, 1247–1255 (2008).
Hoglinger, D. et al. Intracellular sphingosine releases calcium from lysosomes. eLife 4, e10616 (2015).
Taha, T. A. et al. Tumor necrosis factor induces the loss of sphingosine kinase-1 by a cathepsin B-dependent mechanism. J. Biol. Chem. 280, 17196–17202 (2005).
Le Stunff, H. et al. Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J. Biol. Chem. 282, 34372–34380 (2007).
Altuzar, J. et al. Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor. Proc. Natl Acad. Sci. USA 120, e2213886120 (2023).
Hempelmann, P. et al. The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites. Preprint at bioRxiv https://doi.org/10.1101/2023.09.18.557036 (2023).
Ha, H. T. et al. Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models. JCI Insight 9, e175462 (2024).
Wilhelm, L. P. et al. STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. EMBO J. 36, 1412–1433 (2017).
Palladino, E. N. D. et al. Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking. Proc. Natl Acad. Sci. USA 119, e2204396119 (2022).
Platt, F. M., d’Azzo, A., Davidson, B. L., Neufeld, E. F. & Tifft, C. J. Lysosomal storage diseases. Nat. Rev. Dis. Prim. 4, 27 (2018).
Tharkeshwar, A. K. et al. A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency. Sci. Rep. 7, 41408 (2017).
Breiden, B. & Sandhoff, K. Lysosomal glycosphingolipid storage diseases. Annu. Rev. Biochem. 88, 461–485 (2019).
Daum, G. Lipids of mitochondria. Biochim. Biophys. Acta 822, 1–42 (1985).
Fugio, L. B., Coeli-Lacchini, F. B. & Leopoldino, A. M. Sphingolipids and mitochondrial dynamic. Cells 9, 581 (2020).
Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C. & Hannun, Y. A. Ceramide activates heterotrimeric protein phosphatase 2A. J. Biol. Chem. 268, 15523–15530 (1993).
Ruvolo, P. P., Deng, X., Ito, T., Carr, B. K. & May, W. S. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J. Biol. Chem. 274, 20296–20300 (1999).
Mukhopadhyay, A. et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 23, 751–763 (2009).
Bourbon, N. A., Sandirasegarane, L. & Kester, M. Ceramide-induced inhibition of Akt is mediated through protein kinase Cζ: implications for growth arrest. J. Biol. Chem. 277, 3286–3292 (2002).
Birbes, H., El Bawab, S., Hannun, Y. A. & Obeid, L. M. Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J. 15, 2669–2679 (2001).
Siskind, L. J. & Colombini, M. The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem. 275, 38640–38644 (2000).
Lee, H. et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS One 6, e19783 (2011).
Shimeno, H. et al. Partial purification and characterization of sphingosine N-acyltransferase (ceramide synthase) from bovine liver mitochondrion-rich fraction. Lipids 33, 601–605 (1998).
El Bawab, S. et al. Molecular cloning and characterization of a human mitochondrial ceramidase. J. Biol. Chem. 275, 21508–21513 (2000).
Yabu, T., Shimuzu, A. & Yamashita, M. A novel mitochondrial sphingomyelinase in zebrafish cells. J. Biol. Chem. 284, 20349–20363 (2009).
Baden, P. et al. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nat. Commun. 14, 1930 (2023).
Strub, G. M. et al. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J. 25, 600–612 (2011).
Stiban, J., Caputo, L. & Colombini, M. Ceramide synthesis in the endoplasmic reticulum can permeabilize mitochondria to proapoptotic proteins. J. Lipid Res. 49, 625–634 (2008).
Mignard, V. et al. Sphingolipid distribution at mitochondria-associated membranes (MAMs) upon induction of apoptosis. J. Lipid Res. 61, 1025–1037 (2020).
Aaltonen, M. J., Alecu, I., Konig, T., Bennett, S. A. & Shoubridge, E. A. Serine palmitoyltransferase assembles at ER-mitochondria contact sites. Life Sci. Alliance 5, e202101278 (2022).
Planas-Serra, L. et al. Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity. J. Clin. Invest. 133, e162957 (2023).
Tafesse, F. G. et al. Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis. J. Cell Sci. 127, 445–454 (2014).
Walther, T. C., Chung, J. & Farese, R. V. Jr Lipid droplet biogenesis. Annu. Rev. Cell Dev. Biol. 33, 491–510 (2017).
Senkal, C. E. et al. Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metab. 25, 686–697 (2017).
Iqbal, J., Walsh, M. T., Hammad, S. M. & Hussain, M. M. Sphingolipids and lipoproteins in health and metabolic disorders. Trends Endocrinol. Metab. 28, 506–518 (2017).
Verderio, C., Gabrielli, M. & Giussani, P. Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles. J. Lipid Res. 59, 1325–1340 (2018).
Heaver, S. L., Johnson, E. L. & Ley, R. E. Sphingolipids in host-microbial interactions. Curr. Opin. Microbiol. 43, 92–99 (2018).
Vesper, H. et al. Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J. Nutr. 129, 1239–1250 (1999).
Nilsson, A. Metabolism of sphingomyelin in the intestinal tract of the rat. Biochim. Biophys. Acta 164, 575–584 (1968).
Kono, M. et al. Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J. Biol. Chem. 281, 7324–7331 (2006).
Nilsson, A. & Duan, R. D. Absorption and lipoprotein transport of sphingomyelin. J. Lipid Res. 47, 154–171 (2006).
Fukuda, Y., Kihara, A. & Igarashi, Y. Distribution of sphingosine kinase activity in mouse tissues: contribution of SPHK1. Biochem. Biophys. Res. Commun. 309, 155–160 (2003).
Nakahara, K. et al. The Sjogren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway. Mol. Cell 46, 461–471 (2012).
Schmelz, E. M., Crall, K. J., Larocque, R., Dillehay, D. L. & Merrill, A. H. Jr Uptake and metabolism of sphingolipids in isolated intestinal loops of mice. J. Nutr. 124, 702–712 (1994).
Morifuji, M. et al. Milk phospholipids enhance lymphatic absorption of dietary sphingomyelin in lymph-cannulated rats. Lipids 50, 987–996 (2015).
Yamashita, S., Kinoshita, M. & Miyazawa, T. Dietary sphingolipids contribute to health via intestinal maintenance. Int. J. Mol. Sci. 22, 7052 (2021).
Norris, G. H., Milard, M., Michalski, M. C. & Blesso, C. N. Protective properties of milk sphingomyelin against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. J. Nutr. Biochem. 73, 108224 (2019).
Vors, C. et al. Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay. Gut 69, 487–501 (2020).
Le Barz, M. et al. Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women. JCI Insight 6, e146161 (2021).
Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005).
An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014).
Brown, E. M. et al. Bacteroides-derived sphingolipids are critical for maintaining intestinal homeostasis and symbiosis. Cell Host Microbe 25, 668–680.e7 (2019).
Johnson, E. L. et al. Sphingolipids produced by gut bacteria enter host metabolic pathways impacting ceramide levels. Nat. Commun. 11, 2471 (2020).
Le, H. H., Lee, M. T., Besler, K. R. & Johnson, E. L. Host hepatic metabolism is modulated by gut microbiota-derived sphingolipids. Cell Host Microbe 30, 798–808.e7 (2022).
Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549, 48–53 (2017).
Possemiers, S., Van Camp, J., Bolca, S. & Verstraete, W. Characterization of the bactericidal effect of dietary sphingosine and its activity under intestinal conditions. Int. J. Food Microbiol. 105, 59–70 (2005).
Sprong, R. C., Hulstein, M. F. & Van der Meer, R. Bactericidal activities of milk lipids. Antimicrob. Agents Chemother. 45, 1298–1301 (2001).
Norris, G. H., Jiang, C., Ryan, J., Porter, C. M. & Blesso, C. N. Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat diet-fed mice. J. Nutr. Biochem. 30, 93–101 (2016).
Milard, M. et al. Milk polar lipids in a high-fat diet can prevent body weight gain: modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids. Mol. Nutr. Food Res. 63, e1801078 (2019).
Lee, M. T., Le, H. H. & Johnson, E. L. Dietary sphinganine is selectively assimilated by members of the mammalian gut microbiome. J. Lipid Res. 62, 100034 (2021).
Bowden, J. A. et al. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-metabolites in frozen human plasma. J. Lipid Res. 58, 2275–2288 (2017).
Hammad, S. M. et al. Blood sphingolipidomics in healthy humans: impact of sample collection methodology. J. Lipid Res. 51, 3074–3087 (2010).
Iqbal, J. et al. Microsomal triglyceride transfer protein transfers and determines plasma concentrations of ceramide and sphingomyelin but not glycosylceramide. J. Biol. Chem. 290, 25863–25875 (2015).
Hussain, M. M., Shi, J. & Dreizen, P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J. Lipid Res. 44, 22–32 (2003).
Li, Z. et al. Liver-specific deficiency of serine palmitoyltransferase subunit 2 decreases plasma sphingomyelin and increases apolipoprotein E levels. J. Biol. Chem. 284, 27010–27019 (2009).
Maric, J., Kiss, R. S., Franklin, V. & Marcel, Y. L. Intracellular lipidation of newly synthesized apolipoprotein A-I in primary murine hepatocytes. J. Biol. Chem. 280, 39942–39949 (2005).
Choi, H. Y. et al. Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease. J. Biol. Chem. 278, 32569–32577 (2003).
Hotta, N., Abe-Dohmae, S., Taguchi, R. & Yokoyama, S. Preferential incorporation of shorter and less unsaturated acyl phospholipids into high density lipoprotein-like particles in the ABCA1- and ABCA7-mediated biogenesis with apoA-I. Chem. Phys. Lipids 187, 1–9 (2015).
Kersten, S. Physiological regulation of lipoprotein lipase. Biochim. Biophys. Acta 1841, 919–933 (2014).
Illingworth, D. R. & Portman, O. W. Exchange of phospholipids between low and high density lipoproteins of squirrel monkeys. J. Lipid Res. 13, 220–227 (1972).
Rao, R., Albers, J. J., Wolfbauer, G. & Pownall, H. J. Molecular and macromolecular specificity of human plasma phospholipid transfer protein. Biochemistry 36, 3645–3653 (1997).
Jiang, X. C. et al. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J. Clin. Invest. 103, 907–914 (1999).
Qin, S. et al. Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins. J. Lipid Res. 41, 269–276 (2000).
Bentejac, M., Bugaut, M., Delachambre, M. C. & Lecerf, J. Metabolic fate of sphingomyelin of high-density lipoprotein in rat plasma. Lipids 25, 653–660 (1990).
Jeong, T. et al. Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase. J. Clin. Invest. 101, 905–912 (1998).
Lee, J. Y. et al. Functional LCAT deficiency in human apolipoprotein A-I transgenic, SR-BI knockout mice. J. Lipid Res. 48, 1052–1061 (2007).
Li, Z. et al. Effect of total SMS activity on LDL catabolism in mice. Arterioscler. Thromb. Vasc. Biol. 43, 1251–1261 (2023).
van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).
Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).
Menck, K. et al. Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. J. Extracell. Vesicles 6, 1378056 (2017).
Yuyama, K., Sun, H., Mitsutake, S. & Igarashi, Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J. Biol. Chem. 287, 10977–10989 (2012).
Crivelli, S. M. et al. Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles. J. Extracell. Vesicles 11, e12233 (2022).
Kajimoto, T. et al. Involvement of Gβγ subunits of Gi protein coupled with S1P receptor on multivesicular endosomes in F-actin formation and cargo sorting into exosomes. J. Biol. Chem. 293, 245–253 (2018).
Yuyama, K. et al. Decreased amyloid-beta pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 289, 24488–24498 (2014).
Wang, R. et al. Exosome adherence and internalization by hepatic stellate cells triggers sphingosine 1-phosphate-dependent migration. J. Biol. Chem. 290, 30684–30696 (2015).
Kuo, A. et al. Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis. eLife 11, e78861 (2022).
Hammad, S. M. & Lopes-Virella, M. F. Circulating sphingolipids in insulin resistance, diabetes and associated complications. Int. J. Mol. Sci. 24, 4015 (2023).
van Kruining, D. et al. Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods. Adv. Drug Deliv. Rev. 159, 232–244 (2020).
Tang, H., Huang, X. & Pang, S. Regulation of the lysosome by sphingolipids: potential role in aging. J. Biol. Chem. 298, 102118 (2022).
Summers, S. A., Chaurasia, B. & Holland, W. L. Metabolic messengers: ceramides. Nat. Metab. 1, 1051–1058 (2019).
Meikle, P. J. et al. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 31, 2723–2732 (2011).
Laaksonen, R. et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. Eur. Heart J. 37, 1967–1976 (2016).
Havulinna, A. S. et al. Circulating ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 cohort. Arterioscler. Thromb. Vasc. Biol. 36, 2424–2430 (2016).
Hilvo, M. et al. Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients. Eur. Heart J. 41, 371–380 (2020).
Igarashi, J., Thatte, H. S., Prabhakar, P., Golan, D. E. & Michel, T. Calcium-independent activation of endothelial nitric oxide synthase by ceramide. Proc. Natl Acad. Sci. USA 96, 12583–12588 (1999).
SenthilKumar, G. et al. Necessary role of ceramides in the human microvascular endothelium during health and disease. Circ. Res. 134, 81–96 (2024).
Choi, R. H., Tatum, S. M., Symons, J. D., Summers, S. A. & Holland, W. L. Ceramides and other sphingolipids as drivers of cardiovascular disease. Nat. Rev. Cardiol. 18, 701–711 (2021).
Cartier, A. & Hla, T. Sphingosine 1-phosphate: lipid signaling in pathology and therapy. Science 366, eaar5551 (2019).
Ding, G. et al. Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J. Biol. Chem. 282, 27493–27502 (2007).
Maceyka, M. et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J. Biol. Chem. 280, 37118–37129 (2005).
Johnson, K. R., Becker, K. P., Facchinetti, M. M., Hannun, Y. A. & Obeid, L. M. PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J. Biol. Chem. 277, 35257–35262 (2002).
Pitson, S. M. et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22, 5491–5500 (2003).
ter Braak, M. et al. Gαq-mediated plasma membrane translocation of sphingosine kinase-1 and cross-activation of S1P receptors. Biochim. Biophys. Acta 1791, 357–370 (2009).
Venkataraman, K. et al. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem. J. 397, 461–471 (2006).
Soldi, R. et al. Sphingosine kinase 1 is a critical component of the copper-dependent FGF1 export pathway. Exp. Cell Res. 313, 3308–3318 (2007).
Kawahara, A. et al. The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors. Science 323, 524–527 (2009).
Hisano, Y., Kobayashi, N., Yamaguchi, A. & Nishi, T. Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS One 7, e38941 (2012).
Vu, T. M. et al. Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets. Nature 550, 524–528 (2017).
Kobayashi, N. et al. MFSD2B is a sphingosine 1-phosphate transporter in erythroid cells. Sci. Rep. 8, 4969 (2018).
Xu, N. & Dahlback, B. A novel human apolipoprotein (apoM). J. Biol. Chem. 274, 31286–31290 (1999).
Christoffersen, C. et al. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc. Natl Acad. Sci. USA 108, 9613–9618 (2011).
Venkataraman, K. et al. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ. Res. 102, 669–676 (2008).
Kharel, Y. et al. Mechanism of sphingosine 1-phosphate clearance from blood. Biochem. J. 477, 925–935 (2020).
Kono, M. et al. Identification of two lipid phosphatases that regulate sphingosine-1-phosphate cellular uptake and recycling. J. Lipid Res. 63, 100225 (2022).
Zhang, N., Zhang, J., Purcell, K. J., Cheng, Y. & Howard, K. The Drosophila protein Wunen repels migrating germ cells. Nature 385, 64–67 (1997).
Starz-Gaiano, M., Cho, N. K., Forbes, A. & Lehmann, R. Spatially restricted activity of a Drosophila lipid phosphatase guides migrating germ cells. Development 128, 983–991 (2001).
Igarashi, N. et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J. Biol. Chem. 278, 46832–46839 (2003).
Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325, 1254–1257 (2009).
Ihlefeld, K., Claas, R. F., Koch, A., Pfeilschifter, J. M. & Meyer Zu Heringdorf, D. Evidence for a link between histone deacetylation and Ca2+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts. Biochem. J. 447, 457–464 (2012).
Hait, N. C. et al. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat. Neurosci. 17, 971–980 (2014).
Hait, N. C. et al. The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer. Oncogenesis 4, e156 (2015).
Yin, P. et al. Glial sphingosine-mediated epigenetic regulation stabilizes synaptic function in Drosophila models of Alzheimer’s disease. J. Neurosci. 43, 6954–6971 (2023).
Ji, X. et al. Sphingolipid metabolism controls mammalian heart regeneration. Cell Metab. 36, 839–856.e8 (2024).
Alvarez, S. E. et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465, 1084–1088 (2010).
Xia, P. et al. Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling. J. Biol. Chem. 277, 7996–8003 (2002).
Etemadi, N. et al. TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of sphingosine kinase 1. eLife 4, e10592 (2015).
Verstockt, B. et al. Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 19, 351–366 (2022).
Burg, N., Salmon, J. E. & Hla, T. Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases. Nat. Rev. Rheumatol. 18, 335–351 (2022).
Chen, H. et al. Structure of S1PR2-heterotrimeric G13 signaling complex. Sci. Adv. 8, eabn0067 (2022).
Maeda, S. et al. Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias. Sci. Adv. 7, eabf5325 (2021).
Lyapina, E. et al. Structural basis for receptor selectivity and inverse agonism in S1P5 receptors. Nat. Commun. 13, 4736 (2022).
Plomgaard, P. et al. Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects. J. Intern. Med. 266, 258–267 (2009).
Kumaraswamy, S. B., Linder, A., Akesson, P. & Dahlback, B. Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes. Crit. Care 16, R60 (2012).
Su, W., Jiao, G., Yang, C. & Ye, Y. Evaluation of apolipoprotein M as a biomarker of coronary artery disease. Clin. Biochem. 42, 365–370 (2009).
Chirinos, J. A. et al. Reduced apolipoprotein M and adverse outcomes across the spectrum of human heart failure. Circulation 141, 1463–1476 (2020).
Marfia, G. et al. Decreased serum level of sphingosine-1-phosphate: a novel predictor of clinical severity in COVID-19. EMBO Mol. Med. 13, e13424 (2021).
Swendeman, S. L. et al. An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci. Signal 10, eaal2722 (2017).
Ding, B. S. et al. HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. JCI Insight 1, e87058 (2016).
Niaudet, C. et al. Therapeutic activation of endothelial sphingosine-1-phosphate receptor 1 by chaperone-bound S1P suppresses proliferative retinal neovascularization. EMBO Mol. Med. 15, e16645 (2023).
Burg, N., Swendeman, S., Worgall, S., Hla, T. & Salmon, J. E. Sphingosine 1-phosphate receptor 1 signaling maintains endothelial cell barrier function and protects against immune complex-induced vascular injury. Arthritis Rheumatol. 70, 1879–1889 (2018).
Fritzemeier, R. et al. Discovery of in vivo active sphingosine-1-phosphate transporter (Spns2) inhibitors. J. Med. Chem. 65, 7656–7681 (2022).
van der Weyden, L. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233–236 (2017).
Lynch, K. R., Thorpe, S. B. & Santos, W. L. Sphingosine kinase inhibitors: a review of patent literature (2006-2015). Expert Opin. Ther. Pat. 26, 1409–1416 (2016).
Bu, Y., Wu, H., Deng, R. & Wang, Y. Therapeutic potential of SphK1 inhibitors based on abnormal expression of sphk1 in inflammatory immune related-diseases. Front. Pharmacol. 12, 733387 (2021).
Wieczorek, I. & Strosznajder, R. P. Recent insight into the role of sphingosine-1-phosphate lyase in neurodegeneration. Int. J. Mol. Sci. 24, 6180 (2023).
Pepe, G. et al. Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington’s disease. Mol. Ther. 31, 282–299 (2023).
Uranbileg, B. et al. Sphingosine 1-phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids. Clin. Transl. Med. 12, e1056 (2022).
Saba, J. D. et al. Genotype/phenotype interactions and first steps toward targeted therapy for sphingosine phosphate lyase insufficiency syndrome. Cell Biochem. Biophys. 79, 547–559 (2021).
Palaiodimou, L. et al. Fabry disease: current and novel therapeutic strategies. a narrative review. Curr. Neuropharmacol. 21, 440–456 (2023).
Fischer, C. L. et al. Antibacterial activity of sphingoid bases and fatty acids against Gram-positive and Gram-negative bacteria. Antimicrob. Agents Chemother. 56, 1157–1161 (2012).
Rollin-Pinheiro, R., Singh, A., Barreto-Bergter, E. & Del Poeta, M. Sphingolipids as targets for treatment of fungal infections. Future Med. Chem. 8, 1469–1484 (2016).
Caputo, S. et al. Design, synthesis, and biological evaluation of a series of oxazolone carboxamides as a novel class of acid ceramidase inhibitors. J. Med. Chem. 63, 15821–15851 (2020).
Yi, X. et al. Therapeutic potential of the sphingosine kinase 1 inhibitor, PF-543. Biomed. Pharmacother. 163, 114401 (2023).
Kumar, A., Zamora-Pineda, J., Degagne, E. & Saba, J. D. S1P lyase regulation of thymic egress and oncogenic inflammatory signaling. Mediators Inflamm. 2017, 7685142 (2017).
Ikushiro, H. et al. Structural insights into the enzymatic mechanism of serine palmitoyltransferase from Sphingobacterium multivorum. J. Biochem. 146, 549–562 (2009).
Wang, Y. et al. Structural insights into the regulation of human serine palmitoyltransferase complexes. Nat. Struct. Mol. Biol. 28, 240–248 (2021).
Li, S., Xie, T., Liu, P., Wang, L. & Gong, X. Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex. Nat. Struct. Mol. Biol. 28, 249–257 (2021).
Liu, P. et al. Mechanism of sphingolipid homeostasis revealed by structural analysis of Arabidopsis SPT-ORM1 complex. Sci. Adv. 9, eadg0728 (2023).
Schafer, J. H. et al. Structure of the ceramide-bound SPOTS complex. Nat. Commun. 14, 6196 (2023).
Roelants, F. M., Breslow, D. K., Muir, A., Weissman, J. S. & Thorner, J. Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 108, 19222–19227 (2011).
Sun, Y. et al. Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways. Mol. Biol. Cell 23, 2388–2398 (2012).
Sasset, L. et al. Sphingosine-1-phosphate controls endothelial sphingolipid homeostasis via ORMDL. EMBO Rep. 24, e54689 (2023).
Cantalupo, A. et al. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat. Med. 21, 1028–1037 (2015).
Bejaoui, K. et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat. Genet. 27, 261–262 (2001).
Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M. & Nicholson, G. A. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat. Genet. 27, 309–312 (2001).
Gantner, M. L. et al. Serine and lipid metabolism in macular disease and peripheral neuropathy. N. Engl. J. Med. 381, 1422–1433 (2019).
Ikushiro, H. et al. Structural insights into the substrate recognition of serine palmitoyltransferase from Sphingobacterium multivorum. J. Biol. Chem. 299, 104684 (2023).
Gable, K. et al. A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J. Biol. Chem. 285, 22846–22852 (2010).
Penno, A. et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J. Biol. Chem. 285, 11178–11187 (2010).
Garofalo, K. et al. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J. Clin. Invest. 121, 4735–4745 (2011).
Fridman, V. et al. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. Neurology 92, e359–e370 (2019).
Othman, A. et al. Plasma 1-deoxysphingolipids are predictive biomarkers for type 2 diabetes mellitus. BMJ Open Diabetes Res. Care 3, e000073 (2015).
Handzlik, M. K. et al. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature 614, 118–124 (2023).
Muthusamy, T. et al. Serine restriction alters sphingolipid diversity to constrain tumour growth. Nature 586, 790–795 (2020).
Alecu, I. et al. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction. J. Lipid Res. 58, 42–59 (2017).
Rosarda, J. D. et al. Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity. Nat. Commun. 14, 4119 (2023).
Lauterbach, M. A. et al. 1-Deoxysphingolipids cause autophagosome and lysosome accumulation and trigger NLRP3 inflammasome activation. Autophagy 17, 1947–1961 (2021).
Alecu, I. et al. Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway. J. Lipid Res. 58, 60–71 (2017).
Karsai, G. et al. FADS3 is a Delta14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome. J. Biol. Chem. 295, 1889–1897 (2020).
Wang, T. et al. 1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Dev. Cell 56, 3128–3145.e15 (2021).
Kobayashi, N., Kobayashi, N., Yamaguchi, A. & Nishi, T. Characterization of the ATP-dependent sphingosine 1-phosphate transporter in rat erythrocytes. J. Biol. Chem. 284, 21192–21200 (2009).
Mitra, P. et al. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc. Natl Acad. Sci. USA 103, 16394–16399 (2006).
Fukuhara, S. et al. The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. J. Clin. Invest. 122, 1416–1426 (2012).
Nguyen, T. Q. et al. Erythrocytes efficiently utilize exogenous sphingosines for S1P synthesis and export via Mfsd2b. J. Biol. Chem. 296, 100201 (2021).
Le, T. N. U. et al. Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock. Cell Rep. 40, 111208 (2022).
Tang, H. et al. The solute carrier SPNS2 recruits PI(4,5)P(2) to synergistically regulate transport of sphingosine-1-phosphate. Mol. Cell 83, 2739–2752.e5 (2023).
Murata, N. et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem. J. 352, 809–815 (2000).
Christensen, P. M. et al. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J. 30, 2351–2359 (2016).
Del Gaudio, I. et al. Endothelial Spns2 and ApoM regulation of vascular tone and hypertension via sphingosine-1-phosphate. J. Am. Heart Assoc. 10, e021261 (2021).
Obinata, H. et al. Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice. J. Lipid Res. 60, 1912–1921 (2019).
Fleming, J. K., Glass, T. R., Lackie, S. J. & Wojciak, J. M. A novel approach for measuring sphingosine-1-phosphate and lysophosphatidic acid binding to carrier proteins using monoclonal antibodies and the kinetic exclusion assay. J. Lipid Res. 57, 1737–1747 (2016).
Galvani, S. et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci. Signal. 8, ra79 (2015).
Huang, X. S., Zhao, S. P., Hu, M. & Luo, Y. P. Apolipoprotein M likely extends its anti-atherogenesis via anti-inflammation. Med. Hypotheses 69, 136–140 (2007).
Schwab, S. R. et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735–1739 (2005).
Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).
Okuniewska, M. et al. SPNS2 enables T cell egress from lymph nodes during an immune response. Cell Rep. 36, 109368 (2021).
Breart, B. et al. Lipid phosphate phosphatase 3 enables efficient thymic egress. J. Exp. Med. 208, 1267–1278 (2011).
Baeyens, A. et al. Monocyte-derived S1P in the lymph node regulates immune responses. Nature 592, 290–295 (2021).
Mendoza, A. et al. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546, 158–161 (2017).
Dixit, D. et al. S1PR1 inhibition induces pro-apoptotic signaling in T cells and limits humoral responses within lymph nodes. J. Clin. Invest. 134, e174984 (2024).
Acknowledgements
A.K. is supported in part by a postdoctoral fellowship from the American Heart Association. T.H. acknowledges the support of National Institutes of Health grants (R01EY031715, R01AI173377, R01AG078602 and R35HL135821).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
T.H. is an inventor on patents and a patent application on S1P chaperones and S1PR modulations.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks Long Nguyen, Giovanni D’Angelo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Atherogenic
-
Substances or conditions that promote the development of atherosclerosis, a disease characterized by the build-up of plaque in arterial walls, leading to narrowing and potential blockages in blood vessels.
- Brush border
-
A dense layer of microvilli on the surface of enterocytes, increasing their surface area for absorption of nutrients from the digestive tract.
- Caveolae
-
Small invaginations in the plasma membrane of cells, serving as specialized lipid rafts involved in various cellular processes such as signal transduction and vesicular trafficking.
- Childhood amyotrophic lateral sclerosis
-
A rare neurodegenerative disorder that affects motor neurons in children, leading to progressive muscle weakness and loss of motor function.
- Chylomicrons
-
Large lipoprotein particles with a diameter typically ranging from 75 to 1,200 nm, primarily composed of apolipoprotein B48, responsible for transporting dietary triglycerides from the intestine to various tissues throughout the body.
- Docosahexaenoic acid
-
A type of omega-3 essential fatty acid with a double bond at C3 and C4 that is enriched in the brain, retina, and skin and is crucial for brain development, cognitive function, and overall health.
- Gangliosides
-
A class of glycosphingolipids primarily found in cell membranes, particularly abundant in nerve cells, containing one or more sialic acids on their sugar moiety. These have essential roles in cell signalling and neuronal development.
- Globosides
-
A class of glycosphingolipids characterized by a common tetrasaccharide core structure containing a terminal Galα1–4Galβ1–4Glcβ1–1Cer motif, frequently observed in biological membranes and involved in various physiological functions.
- Hereditary spastic paraplegia
-
A group of genetic disorders characterized by progressive stiffness and weakness in the lower limbs due to degeneration of the nerves controlling muscle movement.
- Hexosylceramide
-
A class of glycosphingolipids consisting of a hexose linked to the 1-OH group of the ceramide as the monosaccharide, playing essential roles in cell structure and signalling.
- High-density lipoprotein
-
(HDL). A lipoprotein particle with a diameter ranging from 5 to 12 nm, primarily composed of apolipoprotein A-I, transporting cholesterol from tissues back to the liver for excretion, and is known to reduce the risk of cardiovascular disease.
- Homeodomain
-
A protein motif that binds to specific DNA sequences, regulating gene expression and playing crucial roles in embryonic development and cell differentiation.
- Human leukocyte antigen class I
-
A class of proteins on the cell surface that have a critical role in immune system recognition and response by presenting antigenic peptides to cytotoxic T cells.
- Invariant natural killer T cells
-
A distinct population of T cells that express an invariant T cell receptor and recognize glycosphingolipids, such as α-galactosylceramide, to modulate immune responses.
- Lipid rafts
-
Cholesterol-enriched lipid microdomains in cell membranes that play key roles in organizing signalling molecules and facilitating various cellular processes such as signal transduction and membrane trafficking.
- Low-density lipoprotein
-
(LDL). A lipoprotein particle with a diameter ranging from 18 to 25 nm, primarily composed of apolipoprotein B100, carrying cholesterol from the liver to tissues, high levels of which are associated with an increased risk of cardiovascular disease.
- Membrane contact sites
-
(MCS). Specialized regions where the membranes of two organelles come into close proximity, facilitating direct communication and transfer of lipids, ions, and other molecules between them.
- Milk polar lipid supplementation
-
A dietary supplementation of specific polar lipids derived from milk, including enriched glycerophospholipids and sphingolipids, that may confer various health benefits such as improved lipid metabolism and gut health.
- Multivesicular bodies
-
A cellular structure involved in the sorting and trafficking of proteins and lipids, characterized by multiple internal vesicles enclosed within a single membrane.
- Niemann–Pick disease
-
A group of disorders caused by acid sphingomyelinase deficiency, where abnormal amounts of sphingolipids are accumulated in the lysosome, damaging various tissues.
- Schwann cells
-
Specialized glial cells in the peripheral nervous system that wrap around axons to form myelin sheaths, facilitating rapid conduction of nerve impulses.
- Sterol regulatory element-binding proteins
-
A family of membrane-bound proteins that act as transcription factors to regulate cholesterol and fatty acid synthesis.
- Unfolded protein response
-
A cellular mechanism that regulates the folding capacity of the endoplasmic reticulum and manages unfolded or misfolded proteins, aiming to restore protein homeostasis.
- Very-low-density lipoprotein
-
(VLDL). A lipoprotein particle with a diameter ranging from 30 to 80 nm, primarily responsible for transporting triglycerides synthesized in the liver to peripheral tissues, and is metabolized to form LDL particles.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kuo, A., Hla, T. Regulation of cellular and systemic sphingolipid homeostasis. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00742-y
Accepted:
Published:
DOI: https://doi.org/10.1038/s41580-024-00742-y
