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Sphingomyelin
Sphingomyelin
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General structures of sphingolipids

Sphingomyelin (SPH, /ˌsfɪŋɡoʊˈmaɪəlɪn/) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids.[1][2] In humans, SPH represents ~85% of all sphingolipids, and typically makes up 10–20 mol % of plasma membrane lipids.

Sphingomyelin was first isolated by German chemist Johann L.W. Thudicum in the 1880s.[3] The structure of sphingomyelin was first reported in 1927 as N-acyl-sphingosine-1-phosphorylcholine.[3] Sphingomyelin content in mammals ranges from 2 to 15% in most tissues, with higher concentrations found in nerve tissues, red blood cells, and the ocular lenses. Sphingomyelin has significant structural and functional roles in the cell. It is a plasma membrane component and participates in many signaling pathways. The metabolism of sphingomyelin creates many products that play significant roles in the cell.[3]

Physical characteristics

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Sphingomyelin
Black: Sphingosine
Red: Phosphocholine
Blue: Fatty acid
Top-down view of sphingomyelin, demonstrating its nearly cylindrical shape

Composition

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Sphingomyelin consists of a phosphocholine head group, a sphingosine, and a fatty acid. It is one of the few membrane phospholipids not synthesized from glycerol. The sphingosine and fatty acid can collectively be categorized as a ceramide. This composition allows sphingomyelin to play significant roles in signaling pathways: the degradation and synthesis of sphingomyelin produce important second messengers for signal transduction.

Sphingomyelin obtained from natural sources, such as eggs or bovine brain, contains fatty acids of various chain length. Sphingomyelin with set chain length, such as palmitoylsphingomyelin with a saturated 16 acyl chain, is available commercially.[4]

Properties

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Ideally, sphingomyelin molecules are shaped like a cylinder, however many molecules of sphingomyelin have a significant chain mismatch (the lengths of the two hydrophobic chains are significantly different).[5] The hydrophobic chains of sphingomyelin tend to be much more saturated than other phospholipids. The main transition phase temperature of sphingomyelins is also higher compared to the phase transition temperature of similar phospholipids, near 37 °C. This can introduce lateral heterogeneity in the membrane, generating domains in the membrane bilayer.[5]

Sphingomyelin undergoes significant interactions with cholesterol. Cholesterol has the ability to eliminate the liquid to solid phase transition in phospholipids. Due to sphingomyelin transition temperature being within physiological temperature ranges, cholesterol can play a significant role in the phase of sphingomyelin. Sphingomyelin are also more prone to intermolecular hydrogen bonding than other phospholipids.[6]

Location

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Sphingomyelin is synthesized at the endoplasmic reticulum (ER), where it can be found in low amounts, and at the trans Golgi. It is enriched at the plasma membrane with a greater concentration on the outer than the inner leaflet.[7] The Golgi complex represents an intermediate between the ER and plasma membrane, with slightly higher concentrations towards the trans side.[8]

Metabolism

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Synthesis

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The synthesis of sphingomyelin involves the enzymatic transfer of a phosphocholine from phosphatidylcholine to a ceramide. The first committed step of sphingomyelin synthesis involves the condensation of L-serine and palmitoyl-CoA. This reaction is catalyzed by serine palmitoyltransferase. The product of this reaction is reduced, yielding dihydrosphingosine. The dihydrosphingosine undergoes N-acylation followed by desaturation to yield a ceramide. Each one of these reactions occurs at the cytosolic surface of the endoplasmic reticulum. The ceramide is transported to the Golgi apparatus where it can be converted to sphingomyelin. Sphingomyelin synthase is responsible for the production of sphingomyelin from ceramide. Diacylglycerol is produced as a byproduct when the phosphocholine is transferred.[9]

Sphingomyelin de novo synthesis pathway

Degradation

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Sphingomyelin breakdown is responsible for initiating many universal signaling pathways. It is hydrolyzed by sphingomyelinases (sphingomyelin specific type-C phospholipases).[7] The phosphocholine head group is released into the aqueous environment while the ceramide diffuses through the membrane.

Function

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Membranes

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The membranous myelin sheath that surrounds and electrically insulates many nerve cell axons is particularly rich in sphingomyelin, suggesting its role as an insulator of nerve fibers.[2] The plasma membrane of other cells is also abundant in sphingomyelin, though it is largely to be found in the exoplasmic leaflet of the cell membrane. There is, however, some evidence that there may also be a sphingomyelin pool in the inner leaflet of the membrane.[10][11] Moreover, neutral sphingomyelinase-2 – an enzyme that breaks down sphingomyelin into ceramide – has been found to localise exclusively to the inner leaflet, further suggesting that there may be sphingomyelin present there.[12]

Signal transduction

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The function of sphingomyelin remained unclear until it was found to have a role in signal transduction.[13] It has been discovered that sphingomyelin plays a significant role in cell signaling pathways. The synthesis of sphingomyelin at the plasma membrane by sphingomyelin synthase 2 produces diacylglycerol, which is a lipid-soluble second messenger that can pass along a signal cascade. In addition, the degradation of sphingomyelin can produce ceramide which is involved in the apoptotic signaling pathway.

Apoptosis

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Sphingomyelin has been found to have a role in cell apoptosis by hydrolyzing into ceramide. Studies in the late 1990s had found that ceramide was produced in a variety of conditions leading to apoptosis.[14] It was then hypothesized that sphingomyelin hydrolysis and ceramide signaling were essential in the decision of whether a cell dies. In the early 2000s new studies emerged that defined a new role for sphingomyelin hydrolysis in apoptosis, determining not only when a cell dies but how.[14] After more experimentation it has been shown that if sphingomyelin hydrolysis happens at a sufficiently early point in the pathway the production of ceramide may influence either the rate and form of cell death or work to release blocks on downstream events.[14]

Lipid rafts

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Sphingomyelin, as well as other sphingolipids, are associated with lipid microdomains in the plasma membrane known as lipid rafts. Lipid rafts are characterized by the lipid molecules being in the lipid ordered phase, offering more structure and rigidity compared to the rest of the plasma membrane. In the rafts, the acyl chains have low chain motion but the molecules have high lateral mobility. This order is in part due to the higher transition temperature of sphingolipids as well as the interactions of these lipids with cholesterol. Cholesterol is a relatively small, nonpolar molecule that can fill the space between the sphingolipids that is a result of the large acyl chains. Lipid rafts are thought to be involved in many cell processes, such as membrane sorting and trafficking, signal transduction, and cell polarization.[15] Excessive sphingomyelin in lipid rafts may lead to insulin resistance.[16]

Due to the specific types of lipids in these microdomains, lipid rafts can accumulate certain types of proteins associated with them, thereby increasing the special functions they possess. Lipid rafts have been speculated to be involved in the cascade of cell apoptosis.[17]

Abnormalities and associated diseases

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Sphingomyelin can accumulate in a rare hereditary disease called Niemann–Pick disease, types A and B. It is a genetically-inherited disease caused by a deficiency in the lysosomal enzyme acid sphingomyelinase, which causes the accumulation of sphingomyelin in spleen, liver, lungs, bone marrow, and brain, causing irreversible neurological damage. Of the two types involving sphingomyelinase, type A occurs in infants. It is characterized by jaundice, an enlarged liver, and profound brain damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The brain is not affected. Most patients present with <1% normal levels of the enzyme in comparison to normal levels. A hemolytic protein, lysenin, may be a valuable probe for sphingomyelin detection in cells of Niemann-Pick A patients.[1]

As a result of the autoimmune disease multiple sclerosis (MS), the myelin sheath of neuronal cells in the brain and spinal cord is degraded, resulting in loss of signal transduction capability. MS patients exhibit upregulation of certain cytokines in the cerebrospinal fluid, particularly tumor necrosis factor alpha. This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide; sphingomyelinase activity has been observed in conjunction with cellular apoptosis.[18]

An excess of sphingomyelin in the red blood cell membrane (as in abetalipoproteinemia) causes excess lipid accumulation in the outer leaflet of the red blood cell plasma membrane. This results in abnormally shaped red cells called acanthocytes.

Additional images

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References

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Sphingomyelin

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Sphingomyelin is a sphingophospholipid composed of a backbone—a base linked via an bond to a chain—with a phosphorylcholine head group attached to the C1 position of the sphingosine, making it structurally similar to but with a sphingoid base instead of a backbone. It is one of the most abundant in mammalian cells, serving as a major structural component of plasma membranes, where it contributes to , stability, and the formation of lipid rafts that facilitate protein sorting, signaling, and vesicular trafficking. Particularly enriched in the sheath surrounding nerve fibers, sphingomyelin plays a critical role in neuronal insulation and rapid signal conduction. Beyond its structural functions, sphingomyelin acts as a precursor in the , where it can be hydrolyzed by sphingomyelinases to generate and phosphorylcholine, molecules involved in , , , and stress responses. This is tightly regulated in organelles like the Golgi apparatus and plasma membrane, with sphingomyelin synthases catalyzing its synthesis from and . Dietary sphingomyelin, sourced from foods such as , eggs, and , is absorbed in the intestine and contributes to host pools, supporting gut health, , and potentially neurodevelopment. Dysregulation of sphingomyelin metabolism is implicated in various s; for instance, deficiencies in acid sphingomyelinase lead to sphingomyelin accumulation in lysosomes, causing Niemann-Pick disease types A and B, which manifest as progressive neurodegeneration, , and lung dysfunction. In other contexts, altered sphingomyelin levels are associated with cardiovascular disorders, due to its presence in plasma lipoproteins, and with viral infections, such as hepatitis C, where it supports replication organelle formation. Overall, sphingomyelin's dual roles in membrane architecture and bioactive underscore its essentiality in cellular and disease pathology.

Chemical Structure and Properties

Molecular Composition

Sphingomyelin is classified as a sphingophospholipid, distinguished by its backbone, which consists of a sphingoid base—typically , an 18-carbon amino alcohol with a trans between carbons 4 and 5 (d18:1)—covalently linked to a through an amide bond at the amino group of the sphingoid base. This structure forms the hydrophobic core of the molecule, providing rigidity due to the linear sphingoid base and the linkage, which contrasts with the more flexible ester bonds in other . The hydrophilic head group of sphingomyelin is , attached to the primary hydroxyl group at the C1 position of the via a . This attachment creates an amphipathic molecule with a polar head and nonpolar tails, enabling its integration into lipid bilayers. The fatty acid component exhibits significant variation, commonly ranging from 14 to 26 carbons in length, with C16:0 () and C18:0 () being prevalent, though monounsaturated chains like C24:1 are also common, particularly in neural tissues. These variations influence the molecule's packing properties without altering the core architecture. The general structural formula of sphingomyelin is represented as N-acyl-sphingosine-1-phosphocholine, where the denotes the . A specific example is N-stearoyl-sphingosine-1-phosphocholine (SM d18:1/18:0), which features an 18-carbon base and an 18-carbon saturated , commonly found in mammalian cell membranes. Another representative species is N-palmitoyl-sphingosine-1-phosphocholine (SM d18:1/16:0), highlighting the diversity in acyl chain length. Unlike glycerophospholipids, which rely on a three-carbon backbone esterified to two s and a phosphate-linked head group, sphingomyelin lacks and instead uses the sphingoid base for its single attachment, resulting in a more elongated and rigid structure. In comparison to other , such as glycosphingolipids, sphingomyelin uniquely incorporates the moiety rather than a chain, conferring distinct biochemical properties.

Physical and Chemical Properties

Sphingomyelin (SM) is an amphipathic molecule characterized by a hydrophilic headgroup attached to a hydrophobic moiety, consisting of a backbone linked via an bond to a fatty acyl chain; this structural duality enables SM to self-assemble into lipid bilayers in aqueous environments. The phase behavior of SM is marked by a high main chain-melting transition (T_m), typically ranging from 37°C to 48°C for common saturated species such as N-palmitoyl-SM (T_m ≈ 41°C) and N-stearoyl-SM (T_m ≈ 45°C), attributed to strong van der Waals interactions among the saturated acyl chains and intermolecular hydrogen bonding involving the group and headgroup. In contrast to phosphatidylcholines (PCs), which often exhibit lower T_m values and transition to fluid phases near physiological temperatures, SM tends to maintain ordered phases even at 37°C, resulting in more compact and rigid bilayers due to its enhanced packing efficiency and reduced chain mobility. SM demonstrates low solubility in , with its polar region exhibiting limited hydration compared to PCs (fewer molecules associating with the headgroup due to intramolecular bonding in SM), which contributes to its stability in contexts but necessitates organic solvents like chloroform-methanol mixtures (2:1 v/v) for extraction and solubilization. Chemically, SM exhibits greater resistance to enzymatic and chemical than glycerophospholipids, owing to the robust linkage in its tail versus the more labile bonds in PCs, enhancing its persistence in biological membranes. A notable interaction property of SM is its strong affinity for , facilitated by hydrogen bonding between the sterol's hydroxyl group and SM's or moieties, which promotes the formation of tightly packed, liquid-ordered domains distinct from the liquid-disordered phases observed in PC-cholesterol mixtures. This association is particularly pronounced in SM species with saturated acyl chains of 16-18 carbons, underscoring how chain length subtly modulates these biophysical traits.

Biosynthesis and Metabolism

Biosynthetic Pathways

Sphingomyelin biosynthesis primarily occurs through the de novo pathway, which begins in the (ER) with the condensation of L-serine and palmitoyl-CoA to form 3-ketodihydrosphingosine, catalyzed by serine palmitoyltransferase (SPT). This rate-limiting step involves the core subunits SPTLC1 and SPTLC2, along with accessory subunits like SPTLC3 or small subunits (ssSPTs) that modulate activity, while ORMDL proteins act as inhibitors to regulate flux through the pathway. The intermediate 3-ketodihydrosphingosine is then reduced to sphinganine by 3-ketodihydrosphingosine reductase (KDSR), using NADPH as a cofactor. Subsequent acylation of sphinganine with a fatty , facilitated by one of six ceramide synthase isoforms (CerS1-6), yields dihydroceramide; these enzymes exhibit substrate specificity, with CerS5 and CerS6 preferring shorter-chain fatty acids like palmitoyl-CoA. Dihydroceramide is desaturated by (DEGS1 or DEGS2) to produce , the central precursor for sphingomyelin, completing the ER-localized de novo ceramide synthesis. is transported from the ER to the Golgi apparatus via the CERT protein, where sphingomyelin synthase 1 (SMS1), localized in the trans-Golgi network, transfers a headgroup from to , generating sphingomyelin and diacylglycerol. A second isoform, SMS2, performs the same reaction but is primarily localized to the plasma membrane, contributing to sphingomyelin production at the cell surface. An alternative salvage pathway recycles , derived from the lysosomal degradation of complex , back into through re-acylation by CerS enzymes in the ER, bypassing the initial SPT step and allowing reutilization of sphingoid bases. This pathway supports sphingomyelin under conditions of high sphingolipid turnover. Overall, de novo production predominates in the ER, while final sphingomyelin assembly occurs mainly in the Golgi, with both processes influenced by nutrient availability, such as fatty acids that modulate SPT activity indirectly through ORMDL regulation.

Catabolic Processes

Sphingomyelin primarily occurs through enzymatic mediated by sphingomyelinases (SMases), which cleave the head group from the sphingomyelin backbone, yielding and as primary products. These enzymes are classified based on their optimal and subcellular localization, enabling regulated breakdown in specific cellular compartments. The resulting serves as a central bioactive that can be further metabolized, influencing cellular signaling and . Acid sphingomyelinase (aSMase), encoded by the SMPD1 gene, operates at acidic pH and exists in two forms: lysosomal aSMase (L-aSMase) within endolysosomal compartments and secreted aSMase (S-aSMase) in extracellular spaces. Neutral sphingomyelinase (nSMase), particularly nSMase2 encoded by SMPD2, functions at neutral pH and is localized to the plasma membrane and Golgi apparatus, often within lipid rafts. Alkaline sphingomyelinase (alk-SMase), encoded by ENPP7, is active at alkaline pH and predominantly found in the intestinal mucosa and liver, where it is salt-dependent and crucial for dietary sphingomyelin . Ceramide produced by these SMases undergoes further catabolism by ceramidases, which hydrolyze it into and free fatty acids. is then phosphorylated by sphingosine kinases (SphK1 or SphK2) to form (S1P), a potent signaling involved in , survival, and . This sequential degradation pathway links sphingomyelin breakdown to broader signaling networks. SMase activity is tightly regulated by external stimuli, including tumor necrosis factor-α (TNF-α) and (e.g., ), which activate both acid and neutral isoforms to rapidly generate . Compartmentalization ensures localized effects, as seen in lysosomal accumulation of sphingomyelin due to aSMase deficiency in conditions like Niemann-Pick disease, highlighting the enzyme's role in intracellular trafficking and storage. Sphingomyelin turnover is dynamic, occurring rapidly in response to signals with half-lives varying from hours to days across cell types, such as rapid readjustment in (half-maximal within minutes) versus slower pools in neural tissues (up to 14-69 days).

Distribution and Localization

Cellular and Subcellular Locations

Sphingomyelin is predominantly enriched in the outer leaflet of the plasma membrane in mammalian cells, where it constitutes approximately 10-20% of total phospholipids, contributing to membrane and stability. This asymmetric distribution is maintained by ATP-dependent transporters such as ABC transporters, ensuring sphingomyelin's localization primarily in the exoplasmic leaflet while minimizing its presence in the cytoplasmic leaflet. Within the cell, sphingomyelin is synthesized in the Golgi apparatus, where sphingomyelin synthase enzymes transfer from to . It is also present in endosomes and lysosomes, serving as sites for its degradation by sphingomyelinases into and . In contrast, sphingomyelin levels are low in the and mitochondria, reflecting limited roles in these organelles beyond precursor synthesis. In specialized structures like the myelin sheath of neurons, sphingomyelin is notably abundant, accounting for approximately 10% of and higher in , which supports compact multilayer formation essential for insulation. Its subcellular dynamics can be monitored using fluorescent analogs, such as BODIPY-labeled sphingomyelin, which reveal translocation events during —where sphingomyelin hydrolyzes and redistributes to inner leaflets or mitochondria—and signaling processes involving raft reorganization.

Tissue and Organ Distribution

Sphingomyelin exhibits a heterogeneous distribution across mammalian tissues and organs, with notably high concentrations in the . It is predominant in the sheath formed by in the and Schwann cells in the peripheral nervous system, where it constitutes approximately 25% of total lipids, playing a in electrical insulation of axons. In the lungs, sphingomyelin accounts for about 20% of total phospholipids in lung tissue, contributing to membrane functions. Similarly, in the liver, hepatocytes incorporate sphingomyelin into lipoproteins for assembly and secretion, accounting for roughly 12% of phospholipids. Moderate levels of sphingomyelin are observed in the , , and intestine, typically ranging from 10% to 17% of total phospholipids, with the showing higher enrichment at around 17%. In contrast, concentrations are lower in (approximately 7%) and , where it represents less than 10% of phospholipids, reflecting differences in membrane demands and lipid composition across these sites. Developmentally, sphingomyelin levels in the rise markedly during myelination, increasing from about 2% of total at birth to 15% by age 3 years and stabilizing at peak levels in adulthood, underscoring its association with neural maturation. Across , sphingomyelin is more abundant in mammals than in , particularly in neural tissues, where it supports advanced myelination absent in lower . Dietary sphingomyelin intake also modulates intestinal levels by influencing absorption and local dynamics.

Physiological Roles

Structural Role in Membranes

Sphingomyelin (SM), with its long, saturated acyl chains, contributes to the structural integrity of cellular membranes by promoting ordered lipid packing, which reduces membrane fluidity and permeability. This ordered arrangement arises from the high melting temperature of SM compared to other phospholipids, allowing it to form tightly packed domains that maintain membrane thickness and barrier function. In model bilayers, SM incorporation decreases the area per lipid to approximately 0.43–0.48 nm² and enhances acyl chain order, thereby limiting passive diffusion of ions and molecules across the membrane. The asymmetric distribution of SM, predominantly in the outer leaflet of the plasma membrane alongside phosphatidylcholine, is crucial for maintaining overall bilayer architecture and function. This enrichment in the exoplasmic leaflet, where SM constitutes a significant portion of , helps establish transbilayer that supports through differences in leaflet moments. The zwitterionic headgroup of SM contributes to a positive potential (around 300–400 mV) in the outer leaflet, contrasting with the inner leaflet's anionic and influencing electrostatic interactions that stabilize protein orientation and activity. Such ensures proper topological insertion and function of transmembrane proteins, preventing disruptions that could compromise cellular . SM interacts strongly with via hydrogen bonding and van der Waals forces, forming stoichiometric complexes that further rigidify the membrane and enhance its barrier properties. These interactions increase order and reduce lateral mobility, essential for selective permeability and overall membrane stability. In biological contexts, this complexation helps regulate distribution and supports the membrane's role as a selective barrier.00188-0) In sheaths, high SM content, often alongside galactosylceramide, enables the formation of compact, multilayered structures critical for rapid nerve conduction. SM's presence in promotes tight of bilayers, increasing acyl chain order and impermeability to and ions, which insulates axons effectively. This composition enhances the mechanical resilience of , providing tensile strength against physical stress during neural activity. Overall, asymmetry, including SM's outer leaflet localization, bolsters tensile strength and resistance to mechanical deformation, as demonstrated in erythrocytes where symmetric scrambling reduces stability by twofold under .

Signaling and Transduction Functions

Sphingomyelin serves as a precursor in signaling pathways through its by sphingomyelinases (SMases), generating that acts as a bioactive mediator. Acid sphingomyelinase (ASMase), in particular, hydrolyzes sphingomyelin to produce , which recruits and activates protein kinase C zeta (PKCζ) within lipid microdomains of the plasma membrane.95017-9/fulltext) This leads to the inhibition of Akt () by promoting its dephosphorylation via protein phosphatase 2A, thereby modulating cellular responses to growth factors such as I (IGF-I). Consequently, this pathway attenuates downstream signaling through the PI3K/Akt axis, influencing and survival in response to mitogenic stimuli.87612-1/fulltext) Further downstream in sphingomyelin metabolism, is converted to , which is then phosphorylated by sphingosine kinases to yield (S1P). S1P acts as an extracellular signaling molecule that binds to G-protein-coupled receptors (GPCRs), notably S1PR1, to promote endothelial and vascular maturation during . This receptor-mediated signaling enhances cytoskeletal dynamics and , contributing to vessel stabilization and barrier function in developing vasculature. In the plasma membrane, sphingomyelin facilitates the clustering of transmembrane receptors, thereby enhancing efficiency. For instance, sphingomyelin-enriched domains support the aggregation of (EGFR), enabling its autophosphorylation and activation upon ligand binding, which propagates mitogenic signals. Similarly, sphingomyelin contributes to clustering, promoting formation and mechanotransduction that integrates cues with intracellular pathways like FAK/Src signaling. Within the nucleus, sphingomyelin localizes to the and forms cholesterol-rich microdomains that regulate transcriptional and post-transcriptional processes. Recent investigations have shown that these nuclear sphingomyelin microdomains protect double-stranded from degradation, thereby influencing processing and stability essential for . Additionally, sphingomyelin in these domains interacts with chromatin-modifying factors to modulate acetylation and recruitment, fine-tuning transcription in response to cellular cues. Sphingomyelin engages in cross-talk with other molecules, particularly impacting the PI3K/Akt pathway during inflammatory responses. derived from sphingomyelin antagonizes PI3K activation by inhibiting Akt , which dampens pro-inflammatory production in immune cells such as macrophages. This interaction with phosphoinositides like PIP3 alters membrane recruitment of signaling effectors, thereby balancing inflammatory signaling and preventing excessive immune activation.

Involvement in Programmed Cell Death

Sphingomyelinases (SMases) are activated during apoptosis, leading to the hydrolysis of sphingomyelin into ceramide, a key lipid mediator that promotes cell death signaling. Acid sphingomyelinase (ASMase), in particular, translocates to the plasma membrane or lysosomes upon apoptotic stimuli, generating ceramide that facilitates downstream events such as mitochondrial outer membrane permeabilization (MOMP). Ceramide generated from sphingomyelin hydrolysis induces the release of cytochrome c from mitochondria, which activates the apoptosome and initiates caspase-3 and -9 activation, culminating in the execution phase of apoptosis.87558-0/fulltext) In apoptotic cells, sphingomyelin hydrolysis on the outer leaflet of the contributes to the exposure of (PS), which serves as a primary "eat-me" signal for phagocytic clearance. The accumulation of from sphingomyelin breakdown disrupts membrane asymmetry via activation of scramblases like Xkr8, promoting PS translocation to the outer leaflet and facilitating recognition by expressing receptors such as TIM-4 or Stabilin-2. This process ensures efficient removal of apoptotic bodies without eliciting inflammation, linking sphingomyelin metabolism directly to post-apoptotic engulfment. While predominantly drives pro-apoptotic pathways, intact sphingomyelin can exert anti-apoptotic effects by stabilizing membrane domains that support anti-apoptotic proteins like . In certain cellular contexts, such as during mild stress, unhydrolyzed sphingomyelin maintains integrity, preventing -induced dephosphorylation and inactivation of , thereby inhibiting MOMP and activation. Sphingomyelin's involvement in is evident in both extrinsic and intrinsic pathways. In the extrinsic pathway, tumor necrosis factor-α (TNF-α) rapidly activates neutral and acid SMases, hydrolyzing sphingomyelin to and amplifying death receptor signaling through Fas-associated death domain () recruitment. In the intrinsic pathway, triggers ASMase activation, generating mitochondrial that sensitizes cells to Bax/Bak oligomerization and release. Experimental evidence underscores sphingomyelin's role, as inhibition of SMase activity blocks in neurodegeneration models. For instance, pharmacological inhibition of neutral SMase in serum/glucose-deprived PC-12 neuronal cells prevents ceramide elevation, c-Jun , and caspase-3 , thereby rescuing cell viability. Similarly, ASMase inhibitors reduce -mediated neuronal loss and apoptotic signaling in models by limiting reactive astrocyte-derived extracellular vesicles. These findings highlight SMase as a therapeutic target to modulate in neurodegenerative contexts.

Formation and Function of Lipid Rafts

Sphingomyelin (SM), in complex with , forms the core of lipid rafts, which are dynamic, nanometer-scale microdomains characterized by a liquid-ordered (Lo) phase that contrasts with the surrounding liquid-disordered (Ld) fluid . These domains arise from the preferential partitioning of SM and , where SM's saturated acyl chains and high melting temperature (Tm) promote tight packing and from unsaturated phospholipids in the Ld phase. The interaction is stabilized by hydrogen bonding between SM's headgroups and van der Waals forces with , leading to ordered assemblies that span both leaflets of the bilayer and exhibit elastic deformation while maintaining fluidity. (GPI)-anchored proteins, such as , are recruited to these rafts through transient colocalization and codiffusion with SM, dependent on and GPI anchorage, facilitating protein clustering on timescales of 12–50 ms. Lipid rafts serve as organizing platforms for diverse cellular functions, particularly in immune receptor signaling, where SM-enriched domains concentrate (TCR) components upon activation, enabling rapid compartmentalization of signaling molecules like LAT and PKCθ into rafts for and NFAT pathway initiation. In viral entry and replication, rafts act as entry portals and replication sites; for instance, (HCV) exploits SM-cholesterol rafts to form replication complexes, where SM is essential for maintaining the structural integrity of these factories enriched in viral proteins and . Recent studies confirm SM's critical role in replication, including HCV, by providing host-specific SM species that support viral activity in raft-like Golgi s. Additionally, rafts facilitate through clathrin-independent pathways, such as caveolar and flotillin-dependent mechanisms, where SM aids and sorting for internalization of ligands like EGF. Disruption of raft integrity by SM depletion, often via sphingomyelinase treatment, impairs domain assembly and function, leading to reduced resistance; for example, SM removal from the plasma inhibits influenza virus entry by destabilizing viral-host fusion and decreases phagocytic uptake of fungi via Fcγ receptors. This depletion shifts toward disordered states, hindering trafficking and signaling efficiency. Experimentally, rafts are visualized and isolated as detergent-resistant membranes (DRMs), which retain SM and due to their insolubility in non-ionic detergents like at , serving as a biochemical proxy despite not fully recapitulating native dynamics.

Clinical and Pathological Aspects

Associated Diseases and Disorders

Sphingomyelin dysregulation is prominently implicated in Niemann-Pick disease, a lysosomal storage disorder caused by deficiency of acid sphingomyelinase (ASM), leading to progressive accumulation of sphingomyelin and its precursors in lysosomes across various tissues. In type A, severe ASM deficiency results in early-onset neurodegeneration, characterized by neuronal loss and progressive psychomotor deterioration, often fatal by early childhood, while type B manifests primarily as visceral involvement with , pulmonary infiltration, and milder neurological symptoms. This accumulation disrupts lysosomal function and cellular , contributing to formation in affected organs. In , elevated sphingomyelin levels within arterial plaques enhance vascular and promote formation through activation of sphingomyelinases, which hydrolyze sphingomyelin to generate , a pro-inflammatory mediator that exacerbates and lipid retention. The sphingomyelin- axis facilitates lipid uptake and in the vessel wall, accelerating plaque progression and instability. Neutral sphingomyelinase-2, in particular, drives production in response to inflammatory signals, linking sphingomyelin to cardiometabolic pathology. Alterations in sphingomyelin metabolism contribute to neurological disorders such as Alzheimer's disease, where disrupted sphingomyelin levels in lipid rafts impair amyloid-β processing and promote amyloid plaque formation by altering membrane fluidity and protein trafficking. In Alzheimer's, sphingomyelin synthase disruption leads to intracellular amyloid-β accumulation and cognitive deficits, highlighting sphingomyelin's role in raft-mediated amyloidogenic pathways. For Parkinson's disease, elevated brain sphingomyelin correlates with disease duration and progression, potentially exacerbating mitochondrial dysfunction through ceramide-mediated impairment of energy metabolism and α-synuclein aggregation. Recent lipid profiling studies indicate sphingomyelin pathway dysregulation contributes to mitochondrial bioenergetic failure in Parkinson's, supporting its association with neuronal vulnerability. Sphingomyelin plays a role in metabolic diseases, including and , where sphingomyelin influences insulin signaling by modulating membrane raft composition and generation, thereby promoting . In , altered sphingomyelin levels in and serum exacerbate lipid-induced and impaired , linking high-fat diets to metabolic dysfunction. associated with elevated circulating sphingomyelin species increases cardiovascular risk by fostering atherogenic profiles and endothelial . Infectious diseases involve sphingomyelin in , as seen with (HCV), where sphingomyelin is essential for the RNA replicase complex structure and activates viral polymerase activity, facilitating persistent infection. Inhibition of sphingomyelin synthesis disrupts HCV replication by targeting lipid-dependent viral assembly. For HIV, sphingomyelin enrichment in the supports incorporation and membrane fusion, with neutral sphingomyelinase-2 inhibition impairing virion production and . HIV-1 Gag reorganizes host sphingomyelin-rich domains to optimize formation, underscoring sphingomyelin's role in viral egress.

Therapeutic and Dietary Implications

Enzyme replacement therapy with (Xenpozyme), a recombinant acid sphingomyelinase, has been approved for treating non-central manifestations of acid sphingomyelinase deficiency (ASMD), including Niemann-Pick disease type B, demonstrating improvements in function and reduced and liver volumes in clinical trials. Real-world data from 2024-2025 confirm sustained benefits in adult patients, with enhanced and manageable infusion-related reactions. Inhibitors of sphingomyelin synthase (SMS), such as those targeting SMS2, show preclinical promise in cancer by reducing tumor stemness and promoting accumulation, particularly in models where SMS2 overexpression confers resistance. Dietary sphingomyelin, abundant in and eggs, enhances intestinal by upregulating proteins and modulating composition, thereby reducing permeability in high-fat diet models. It also inhibits absorption in the gut, lowering serum LDL levels more effectively from sources than eggs in studies. Animal models, including rabbits with hypercholesterolemia, indicate that dietary sphingomyelin attenuates progression by decreasing aortic plaque formation and sphingomyelin enrichment in arterial walls. Supplementation with sphingomyelin combined with vitamin D3 exhibits neuroprotective effects in rabbit models, increasing expression and promoting differentiation as observed in 2025 studies. In obesity contexts, sphingomyelin supplements regulate to improve and reduce in high-fat diet-fed mice, potentially mitigating and . Emerging gene therapies using adeno-associated viral vectors to deliver acid sphingomyelinase have shown efficacy in preclinical Niemann-Pick models by correcting lysosomal storage and reducing sphingomyelin accumulation. (S1P) receptor modulators, such as and —analogs derived from sphingomyelin metabolism—reduce relapse rates and delay progression in relapsing through lymphocyte sequestration. Ongoing preclinical and early-phase investigations target sphingomyelin pathways in , with neutral sphingomyelinase-2 inhibitors like PDDC reducing tau pathology and ceramide-induced neurodegeneration in mouse models as of 2024 updates. For , acid sphingomyelinase inhibitors are under exploration to mitigate ceramide-driven , supported by 2025 reviews of their role in , though no large-scale human trials have reported results by late 2025.

References

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