Bioactive sphingolipids constitute a family of lipids, including sphingosine, ceramide, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate. These molecules act on distinct protein targets, including kinases, phosphatases, lipases and other enzymes and membrane receptors, and they exert distinct cellular functions.
This universe of sphingolipids, the sphingolipidome, is highly complex, with distinct molecular species of each of the bioactive lipids and metabolic interconnections that interconvert one bioactive lipid into others (for example, ceramide to sphingosine and then to S1P). Critically, these pathways demonstrate specific subcellular localizations that appear to dictate the specific functions of sphingolipids.
A plethora of cell biological processes are critically modulated by bioactive sphingolipids, including growth regulation, cell migration, adhesion, apoptosis, senescence and inflammatory responses.
At the tissue and organismal level, bioactive sphingolipids have been implicated in neurodegenerative processes, metabolic disorders, various cancers (and various cancer attributes), immune function, cardiovascular disorders and skin integrity.
Major advances have been made in defining the enzymes of sphingolipid metabolism, their mechanisms and their structures. However, a major challenge is to decipher the biochemical mechanisms by which these enzymes and their products are specifically regulated.
A key future challenge is to determine the molecular mechanisms of action for specific species or subgroups of bioactive sphingolipids (for example, distinct ceramides and distinct sphingoid bases).
Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid–protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.
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The authors thank the members of their laboratories and M. Airola, C. Luberto, C. Clarke, D. Canals, C. Senkal, C. Rhein and F. Velazquez for helpful discussions. The authors are very grateful for the contribution of M. Hernandez for assembling table 1 and supplementary information tables S2 and S3. Due to space limitations, the authors have striven to reference the more recent studies pertinent to the presentation while directing the readers to more in-depth targeted reviews. The authors apologize for the multitude of sphingolipid investigators whose works they could not cite in this Review.
The authors declare no competing financial interests.
Bioactive, acidic lipids with various hormone-like activities, including modulation of inflammation, regulation of blood flow and blood pressure and reproduction.
A major subtype of sphingolipids composed of ceramide and an oligosaccharide that contains at least one sialic acid residue.
Acylation of fatty acids at the ω-position (last position) in the acyl chain.
- Freeze–fracture studies
A form of electron microscopy involving freezing in order to preserve lipid membrane structures.
- G protein-coupled receptors
(GPCRs). Heptahelical membrane receptors that bind and regulate G proteins.
A subtype of sphingolipids with a ceramide associated with at least two sugars, but no sialic acid.
- Diauxic shift
The shift in growth from rapid fermentative to aerobic glycolysis.
A type of neural cell arising from macrophages or their precursors that serves supportive and protective functions in the central nervous system.
- ER stress
Endoplasmic reticulum (ER) dysfunction due to stress stimuli that result in increased accumulation of misfolded proteins in the ER.
A regulated form of necrotic cell death associated with immune and inflammatory responses.
- Multiple sclerosis
A degenerative disease of the nervous system associated with a loss of myelination (covering) of axonal sheaths.
- T cell egress
Lymphocyte migration from the thymus and lymph nodes into the bloodstream.
- von Hippel–Lindau (VHL) gene
A gene whose mutations can result in von Hippel–Lindau disease. It encodes a protein that participates in the regulation of the levels of hypoxia-inducible factor (HIF) through degradation.
- Luminal A type breast cancer
A subtype of breast cancer in which the cells appear to resemble most cells of the luminal lining of the breast ducts.
- Insulin resistance
A state in which cells, tissues or organisms fail to respond normally to insulin.
- Glucose intolerance
Also known as impaired glucose tolerance. A pre-diabetic state involving hyperglycaemia and usually poor responsiveness to insulin.
- Hepatic steatosis
Condition associated with non-alcoholic fatty liver disease with increased accumulation of fat in liver cells, usually in the form of triglycerides.
- Ischaemic injury
Tissue and cell injury that results from a decrease in or interruption of the blood supply.
- Reperfusion injury
Injury or damage to tissues resulting from the reoxygenation of previously ischaemic tissues.
- Diabetic neuropathy
Dysfunction of the peripheral and autonomic nervous system that arises from long-standing diabetes.
- Coronary angiography
An invasive procedure using dyes in the bloodstream to visualize the coronary circulation using radiography.
- Osteogenesis imperfecta
A group of genetic disorders characterized by brittle bones.
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Hannun, Y., Obeid, L. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19, 175–191 (2018). https://doi.org/10.1038/nrm.2017.107
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