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Sphingomyelin

Sphingomyelin

Linear Formula

C47H93N2O6P

Synonyms

n/a

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What is Sphingomyelin?

Sphingomyelin belongs to a class of lipids known as sphingolipids, which are characterized by an eighteen-carbon amino-alcohol backbone called sphingosine. These lipids are primarily found in the cell membrane, trans Golgi network, and endoplasmic reticulum of mammalian cells. Sphingolipids are synthesized from various nonsphingolipid precursors, which are then modified by functional groups to produce a variety of sphingolipid species. Sphingomyelin is one of the most abundant species of sphingolipids and sphingomyelin synthesis involves the phosphorylation of ceramide to include a phosphocholine headgroup1.

Sphingomyelin is the predominant sphingolipid in the outer leaflet of cell membranes and plays a crucial role in maintaining plasma membrane structure. Importantly, sphingomyelin is essential for the maintenance of lipid rafts, which are membrane lipid microdomains enriched in sphingolipids and cholesterol. Lipid rafts perform numerous biological functions, including regulation of cell signal transduction pathways, shuttling cell membrane molecules, and enabling the entry of pathogens and toxins2. The critical role of sphingomyelin in mediating essential cellular functions has led many researchers to investigate changes in sphingomyelin levels in various diseases.

Sphingomyelin and Neuroscience

Sphingomyelin is enriched in the brain, where it plays a pivotal role in regulating the myelin sheaths of neurons, an essential structure that facilitates signal transduction between nerve cells. Demyelination and lipid degradation are some of the hallmarks of motor neuron diseases such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy and recent findings have identified aberrant sphingomyelin metabolism as a potential mechanism underlying these diseases.

For example, impaired lipid metabolism has been observed in ALS patients, who exhibit increased spinal cord levels of sphingomyelin. In vitro experiments with cultured motor neurons revealed increased oxidative stress associated with lipid abnormalities and pharmacological inhibition of sphingomyelin synthesis protects against cell death induced by excitotoxic intervention3. Supporting these findings, over 20 risk genes in ALS are also involved in lipid raft homeostasis and sphingolipid pathways4.

Impairments in sphingomyelin metabolism have also been implicated in Alzheimer’s disease (AD). One study found elevated levels of sphingomyelin in the cerebral spinal fluid of individuals with AD dementia. Interestingly, individuals with early AD symptoms exhibit increased sphingomyelin levels compared to cognitively normal controls, while there are no significant changes between mild or moderate AD and controls. These findings suggest that sphingomyelin metabolism can be used as an early biomarker for predicting later AD development5.

Sphingomyelin and Metabolic Health

Alterations in lipid metabolism are closely linked to metabolic disorders such as obesity and diabetes. Recent studies suggests that imbalances in sphingolipid levels and dysfunction in sphingolipid pathways are correlated with obesity and impaired glucose metabolism. For instance, one report showed that obesity parameters (e.g., insulin resistance, high BMI) were associated with elevated levels of sphingomyelin species with saturated acyl chains in obese individuals compared to controls6.

Supporting the importance of sphingomyelin in metabolic health, one study demonstrated that genetic knockout of sphingomyelin synthase 2, the synthetic enzyme for sphingomyelin, protects against diet-induced obesity and insulin resistance. These researchers suggest that inhibiting sphingomyelin synthase 2 protects against obesity by reducing fatty acid uptake and lipid droplet formation7. Others have linked sphingolipid metabolism to obesity-induced inflammation, where inflammatory cytokines promote the hydrolysis of sphingomyelin to ceramide, further exacerbating aberrations in lipid metabolism8.

Sphingomyelin and Cardiovascular Health

Alterations in lipid composition, including changes in triglycerides, cholesterol, low density lipoprotein(LDL), and high density lipoprotein (HDL), have been shown to play a central role in cardiovascular diseases (CVD). While CVD studies have faced challenges in identifying the specific lipid species contributing to CVD development, emerging findings have indicated that changes in sphingomyelin may serve as a early predictor of CVD development. Indeed, recent studies have shown that elevated sphingomyelin levels are a potential independent risk factor for coronary artery disease9.

One lipidomic study examining incident CVD cases revealed changes in particular lipid species that predicted CVD risk. Notably, higher baseline levels of sphingomyelin were associated with increased odds of CVD and elevated LDL-cholesterol. These findings provide evidence for the utility of specific lipid species as biomarkers for CVD prognosis10.

Other reports have shown that sphingomyelin is among a group of bioactive lipids that are elevated in human carotid plaques. This study found that sphingomyelin levels are correlated with inflammatory cytokines and markers of plaque instability. Furthermore, in vitro application of sphingomyelin induces markers of apoptosis11.

Sphingomyelin and Gastrointestinal health

Low levels of sphingomyelin can be found in dairy products, eggs, and meat, prompting researchers to investigate the effects of dietary sphingomyelin on gastrointestinal health. Overall, scientists have found beneficial effects of dietary sphingomyelin on the gut microbiome, which subsequently impacts metabolic health.

In one study, mice fed a high-fat diet supplemented with dietary milk sphingomyelin showed reduced weight gain and decreased serum cholesterol levels. These effects were attributed to protective changes in intestinal barriers, decreased lipopolysaccharides, and beneficial alterations to gut microbiota12. Other studies have demonstrated that the intake of milk sphingomyelin is an effective inhibitor of intestinal cholesterol absorption in rats, providing another benefit to gut health13.

Sphingomyelin and Oncology

The examination of changes in cell surface biochemistry has been integral to understanding cancer initiation, cell growth, and immune evasion. Given the importance of sphingomyelin in regulating plasma membrane function, a growing body of literature has implicated sphingomyelin in playing a significant role in cancer prognosis. Increased levels of sphingomyelin have been reported in several types of cancer14, and genetic manipulation of sphingomyelin pathways has been shown to suppress the survival, growth, and migration of ovarian cancer cell lines15.

Sphingolipids in research

As of March 2024, there are over 16,000 citations for sphingomyelin in research publications (excluding books and documents) on Pubmed. The tremendous number of publications linking this metabolite to a broad range of physiological functions suggests that any research program seeking to better understand neurological, metabolic, cardiovascular, oncological, and gastrointestinal health may benefit from quantitative analysis of sphingomyelin. Considering the importance of sphingomyelin in plasma membrane function, preclinical studies may also benefit from sphingomyelin quantification to further the understanding of biomarkers, diagnosis, and disease monitoring.

References

  1. Gault, CR, Obeid, LM, and Hannun, YA. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 2010;(688):1-23.
  2. Codini, M, Garcia-Gil, M, and Albi, E. Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer. Int J Mol Sci 2021;(22).
  3. Cutler, RG, Pedersen, WA, Camandola, S, et al. Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann Neurol 2002;(52):448-457.
  4. Moll, T, Marshall, JNG, Soni, N, et al. Membrane lipid raft homeostasis is directly linked to neurodegeneration. Essays Biochem 2021;(65):999-1011.
  5. Kosicek, M, Zetterberg, H, Andreasen, N, et al. Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer’s disease. Neurosci Lett 2012;(516):302-305.
  6. Hanamatsu, H, Ohnishi, S, Sakai, S, et al. Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults. Nutr Diabetes 2014;(4):e141.
  7. Mitsutake, S, Zama, K, Yokota, H, et al. Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. J Biol Chem 2011;(286):28544-28555.
  8. Kang, SC, Kim, BR, Lee, SY, et al. Sphingolipid metabolism and obesity-induced inflammation. Front Endocrinol (Lausanne) 2013;(4):67.
  9. Jiang, XC, Paultre, F, Pearson, TA, et al. Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 2000;(20):2614-2618.
  10. Fernandez, C, Sandin, M, Sampaio, JL, et al. Plasma lipid composition and risk of developing cardiovascular disease. PLoS One 2013;(8):e71846.
  11. Edsfeldt, A, Duner, P, Stahlman, M, et al. Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation. Arterioscler Thromb Vasc Biol 2016;(36):1132-1140.
  12. Norris, GH, Jiang, C, Ryan, J, et al. Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat diet-fed mice. J Nutr Biochem 2016;(30):93-101.
  13. Noh, SK, and Koo, SI. Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats. J Nutr 2004;(134):2611-2616.
  14. Tallima, H, Azzazy, HME, and El Ridi, R. Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion. Lipids Health Dis 2021;(20):150.
  15. Don, AS, Lim, XY, and Couttas, TA. Re-configuration of sphingolipid metabolism by oncogenic transformation. Biomolecules 2014;(4):315-353.