Ceramides are sphingolipids that serve as important structural components of cell membranes. Beyond their role as membrane constituents, ceramides are recognized as signaling molecules involved in diverse cellular processes. The balance between ceramide synthesis and degradation is critical for maintaining cellular homeostasis, and dysregulation of ceramide metabolism has been implicated in various pathological conditions, including cancer, neurodegenerative diseases, and metabolic disorders.
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Ceramide Structure
The structure of ceramide molecule has two long-chain alkyl groups, one amide group and two hydroxyl groups, which make the ceramide molecule hydrophilic and hydrophobic, and this property is important for its role in epidermal cuticle moisturization, etc.
Ceramides are composed of long-chain sphingosine covalently bonded to fatty acids through amide bonds. Both sphingosine and fatty acid carbon chains can vary in length, saturation and number of hydroxyl groups. Fatty acids are divided into non-hydroxyl and hydroxyl fatty acids based on the presence or absence of hydroxyl groups in the carbon chain. Sphingosine has three structures; sphingosine containing unsaturated double bonds is called neurosphingosine, saturated sphingosine is called dihydrosphingosine, and sphingosine containing three hydroxyl groups is called phytosphingosine.
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Ceramide Synthesis
Ceramides are synthesized through multiple pathways, with the most common route being the de novo synthesis pathway. In this pathway, serine and palmitoyl-CoA are converted to 3-ketosphinganine through a series of enzymatic reactions involving serine palmitoyltransferase (SPT) and 3-ketosphinganine reductase. Subsequently, 3-ketosphinganine is converted to dihydroceramide by dihydroceramide synthase. Finally, dihydroceramide is desaturated by dihydroceramide desaturase to form ceramide.
In addition to the de novo synthesis pathway, ceramides can also be generated through the salvage pathway, which involves the recycling of sphingosine and sphingosine-1-phosphate (S1P) back to ceramide. This pathway is mediated by ceramide synthases and ceramidases.
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Ceramide Degradation
Ceramide degradation occurs primarily through the action of ceramidases, which hydrolyze ceramide into sphingosine and free fatty acids. Sphingosine can be phosphorylated to form sphingosine-1-phosphate (S1P) by sphingosine kinases, thus connecting ceramide metabolism with the sphingolipid signaling pathway.
The balance between ceramide synthesis and degradation is tightly regulated and determines the overall ceramide levels within cells. Disruptions in this balance can have profound implications for cellular functions and contribute to the development of various diseases.
Pathways of ceramide synthesis and degradation (Wu et al., 2020).
Effects of Ceramides on the Skin
Barrier function
Ceramides play a crucial role in maintaining the integrity and function of the skin barrier. Studies by Grubauer et al. using organic solvents such as acetone to treat the skin of hairless mice aged 1-3 months have shown that as the lipid content in the skin decreases, the skin barrier function declines. Holleran et al. investigated the relationship between skin barrier function and ceramide synthesis using [3H]H2O permeation and found that disruption of the skin barrier function in hairless mice due to acetone treatment leads to an increase in ceramide synthesis. After 5-7 hours of acetone treatment, ceramide synthesis can reach 170%. Skin barrier function and ceramide synthesis return to normal after 24 hours. Therefore, ceramides play a significant role in maintaining skin barrier function.
Adhesive function
Ceramides act as a binding agent between cell surface proteins through ester bonds, forming a "lipid-cell-protein" complex. Smith et al. reported that the adhesion strength between corneocytes (keratinized cells) can be determined by measuring the ceramide content in the stratum corneum. A decrease in ceramide content in the stratum corneum can lead to reduced adhesion between corneocytes, resulting in dryness, flaking, and scaling of the skin. Pawlings et al. studied the mechanism of desquamation in dry skin and found that the main cause of skin dryness is a decrease in ceramide content in the stratum corneum, and the level of ceramides is directly related to the degree of skin dryness. Using ceramides can significantly enhance the adhesion between corneocytes, improving skin dryness and reducing desquamation.
Moisturizing function
The skin contains approximately 18%-20% water by weight, and skin hydration is closely related to skin moisture and elasticity. Excessive loss of skin moisture can lead to dryness and even wrinkling of the skin. Imokawa et al. used organic solvents to remove lipid components from the stratum corneum and found that the skin developed wrinkles, scaling, and a significant decrease in skin conductivity after continuous (>4 days) exposure. Local skin tests were conducted with extracted lipid components from the stratum corneum under the same conditions to determine their effects on skin hydration recovery. The results showed that local application of ceramides significantly increased skin conductivity, followed by cholesterol, while the effects of free fatty acids and cholesterol esters were not significant. Ceramides have a strong ability to bind water molecules and maintain skin hydration by forming a network structure in the stratum corneum. Therefore, ceramides have a moisturizing effect on the skin.
Anti-aging function
During the aging process, lipid synthesis decreases, leading to a decrease in ceramide content in the stratum corneum. The use of ceramides can increase the ceramide content in the stratum corneum, improving conditions such as skin dryness, desquamation, and roughness. Additionally, ceramides can increase the thickness of the stratum corneum, enhance skin water-holding capacity, reduce wrinkles, improve skin elasticity, and delay skin aging.
Possible biological mechanisms involved in ceramide deficiency (Imokawa et al., 2021)
Biological Functions of Ceramides
Involvement in cellular functions
Ceramides are present in the cell membranes of both animal and plant tissues. Their molecules expose monosaccharide or oligosaccharide residues to the extracellular space, participating in reactions with other cells, antibodies, bacterial toxins, and viral envelope proteins. Therefore, ceramides play a crucial role in cell adhesion, immune regulation, blood type determination, and act as tumor antigens. Glycosphingolipids (GSLs) directly participate in cell recognition through GSL-GSL interactions and GSL-lectin interactions. Certain GSLs, such as ganglioside GM, regulate integrin receptor function. In transmembrane signaling, some specific gangliosides directly modulate receptor, tyrosine kinase, and protein kinase C (PKC) activities. Some gangliosides significantly enhance receptor kinase activity, leading to increased MAP kinase activity. Ceramides act as membrane antigens for certain tumors and also serve as receptors for viruses, bacteria, and their toxins. They are regulatory factors for cell-cell, cell-microbe, and cell adhesion protein interactions.
Regulation of cell growth and differentiation
Treatment of HL-60 leukemia cells with C2-ceramide or other water-soluble derivatives can induce cell differentiation. Exogenous ceramides exert similar effects on HL-60 cells as TNF-alpha, 1,25-dihydroxyvitamin D3, and gamma-interferon. C-ceramide (1 μm) and its congeners have specific anti-proliferative effects on HL-60 cells and exhibit anti-leukemic cell activity in other leukemia cells and malignant cells in tissue culture. Ceramides can regulate neuronal cell growth and differentiation as well.
Induction of cell apoptosis
Ceramides act as intracellular regulators of cell cytotoxicity. In bone marrow and lymphocytes, ceramide derivatives cause early and specific DNA fragmentation between nucleosomes, which is an external characteristic of cell apoptosis. Ceramides can regulate TNF-alpha-induced cell apoptosis and participate in other processes of apoptotic cells. The transcription factor AP-1 is crucial for HL-60 cell apoptosis, and ceramides induce cell apoptosis by activating AP-1 and modulating signal transduction.
Role in inflammation
Ceramides regulate the secretion of PGE2 and enhance the secretion of IL-2 in lymphocytes. Furthermore, ceramides modulate the action of TNF-alpha, indicating their ability to regulate immune function and inflammatory responses.
Ceramide Metabolism and Disease
Altered ceramide metabolism has been associated with several diseases and pathological conditions.
- Cancer: Dysregulation of ceramide metabolism has been observed in various types of cancer. Reduced ceramide levels and increased S1P levels have been linked to cancer cell survival, proliferation, and resistance to chemotherapy. Targeting ceramide metabolism pathways has emerged as a potential therapeutic strategy for cancer treatment.
- Neurodegenerative Diseases: Ceramide accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Increased ceramide levels can induce neuronal apoptosis and contribute to neuroinflammation, oxidative stress, and synaptic dysfunction.
- Metabolic Disorders: Ceramide metabolism dysregulation has been associated with metabolic disorders such as obesity and insulin resistance. Elevated ceramide levels in adipose tissue and skeletal muscle have been linked to impaired insulin signaling and the development of type 2 diabetes.
Creative Proteomics offers ceramide analysis based on the LC-MS platform, providing the necessary tools and technical support to study ceramide metabolism. LC-MS enables accurate identification and quantification of different types of ceramides thanks to its high resolution, sensitivity and specificity.
Ceramide analysis using the LC-MS platform allows the exploration of the type, structure, level and association of ceramides with other metabolites. With the separation capability of liquid chromatography, we can effectively separate ceramides from complex mixtures. The high sensitivity and selectivity of mass spectrometry allows for accurate detection and quantification of target ceramides. Insights into the kinetics and regulation of ceramide metabolism can be gained through LC-MS analysis by Creative Proteomics, facilitating the further development of ceramide-related research.
References
- Wu, J. M., & Schulze, P. C. (2020). Cardiovascular prognosis: a new role for ceramides and other cardiometabolites. ESC Heart Failure, 7(6), 3285.
- Imokawa, G. (2021). Cutting edge of the pathogenesis of atopic dermatitis: Sphingomyelin deacylase, the enzyme involved in its ceramide deficiency, plays a pivotal role. International Journal of Molecular Sciences, 22(4), 1613.
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