Ceramide

Pathways for ceramide synthesis

There are three major pathways of ceramide generation. First, the sphingomyelinase pathway uses an enzyme to break down sphingomyelin in the cell membrane and release ceramide. Second, the de novo pathway creates ceramide from less complex molecules. Third, in the "salvage" pathway, sphingolipids that are broken down into sphingosine are reused by reacylation to form ceramide.

Sphingomyelin hydrolysis

Hydrolysis of sphingomyelin is catalyzed by the enzyme sphingomyelinase. Because sphingomyelin is one of the four common phospholipids found in the plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells, the radiation leads to the activation of sphingomyelinase in the cell membrane and ultimately, to ceramide generation.

De novo

De novo synthesis of ceramide begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine. This reaction is catalyzed by the enzyme serine palmitoyl transferase and is the rate-limiting step of the pathway. In turn, 3-keto-dihydrosphingosine is reduced to dihydrosphingosine, which is then followed by acylation by the enzyme (dihydro)ceramide synthase to produce dihydroceramide. The final reaction to produce ceramide is catalyzed by dihydroceramide desaturase. De novo synthesis of ceramide occurs in the endoplasmic reticulum. Ceramide is subsequently transported to the Golgi apparatus by either vesicular trafficking or the ceramide transfer protein CERT. Once in the Golgi apparatus, ceramide can be further metabolized to other sphingolipids, such as sphingomyelin and the complex glycosphingolipids.

Salvage pathway

Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the lysosomes, with the end goal of producing sphingosine. In the case of glycosphingolipids, exohydrolases acting at acidic pH optima cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains, leaving just the sphingosine portion of the molecule, which may then contribute to the generation of ceramides. Ceramide can be further hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which are able to leave the lysosome, unlike ceramide. The long-chain sphingoid bases released from the lysosome may then re-enter pathways for synthesis of ceramide and/or sphingosine-1-phosphate. The salvage pathway re-utilizes long-chain sphingoid bases to form ceramide through the action of ceramide synthase. Thus, ceramide synthase family members probably trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes. The salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis.

Physiological roles

Pathology

As a bioactive lipid, ceramide has been implicated in a variety of physiological functions including apoptosis, cell growth arrest, differentiation, cell senescence, cell migration and adhesion. Roles for ceramide and its downstream metabolites have also been suggested in a number of pathological states including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation.

Several distinct ceramides potently predict major adverse cardiovascular events (MACE), namely C16:0, C18:0, and C24:1, although C24:0 has an inverse relationship. C16-C18 are harmful in the liver. Ceramide levels are positively correlated with inflammation and oxidative stress in the liver, and the onset and progression of non-alcoholic fatty liver disease (NAFLD) is associated with elevated ceramide in hepatocytes. Dietary intake of saturated fat has been shown to increase serum ceramide and increase insulin resistance. Although initial studies showed increased insulin resistance in muscle, subsequent studies also showed increased insulin resistance in liver and adipose tissue. Interventions that limit ceramide synthesis or increase ceramide degradation lead to improved health (reduced insulin resistance and reduced fatty liver disease, for example).

Ceramides induce skeletal muscle insulin resistance when synthesized as a result of saturated fat activation of TLR4 receptors. Unsaturated fat does not have this effect. Ceramides induce insulin resistance in many tissues by inhibition of Akt/PKB signaling. Aggregation of LDL cholesterol by ceramide causes LDL retention in arterial walls, leading to atherosclerosis. Ceramides cause endothelial dysfunction by activating protein phosphatase 2 (PP2A). In mitochondria, ceramide suppresses the electron transport chain and induces production of reactive oxygen species.

Apoptosis

One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. Apoptosis, or Type I programmed cell death, is essential for the maintenance of normal cellular homeostasis and is an important physiological response to many forms of cellular stress. Ceramide accumulation has been found following treatment of cells with a number of apoptotic agents, including ionizing radiation, UV light, TNF-alpha, and chemotherapeutic agents. This suggests a role for ceramide in the biological responses of all these agents. Because of its apoptosis-inducing effects in cancer cells, ceramide has been termed the "tumor suppressor lipid". Several studies have attempted to define further the specific role of ceramide in the events of cell death and some evidence suggests ceramide functions upstream of the mitochondria in inducing apoptosis. However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive.

Skin

The stratum corneum is the outermost layer of the epidermis. It is composed of terminally differentiated and enucleated corneocytes that reside within a lipid matrix, like "bricks and mortar." Together with cholesterol and free fatty acids, ceramides form the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (50% by weight), cholesterol ( 25% by weight), and free fatty acids (~15% by weight), with smaller quantities of other lipids also being present. The lipid barrier also protects against the entry of microorganisms.

Epidermal ceramides have a diversity of structures and can be broadly classified as AS and NS ceramides; ADS and NDS dihydroceramides; AH, EOH, and NH 6-hydroxyceramides; AP and NP phytoceramides; and EOH and EOS acylceramides, see figure.

Similar to body site-specific alterations in ceramide abundance, there are also well-characterized changes in epidermal ceramide expression in patients with inflammatory skin diseases. In the hyperplastic disorder psoriasis, investigators have reported an increase in AS and NS ceramides and a decrease in EOS, AP, and NP ceramides, which may contribute to a defect in the skin's water impermeability barrier. Studying ceramide expression in atopic dermatitis and psoriasis patients, other investigators have reported that rather than focusing on ceramide classes, ceramide sphingoid base length and fatty acid chain length have the strongest influence on the likelihood of a particular ceramide structure being upregulated or downregulated in inflamed skin. Ceramide levels in the skin, hair, and nails can be reduced due to environmental changes (such as dry/polluted air), use of harsh sulfates, excessive heat (including heat styling), UV exposure, and biological aging.

Hormonal

Inhibition of ceramide synthesis with myriocin in obese mice may lead to both improved leptin signaling and decreased insulin resistance by decreasing SOCS-3 expression. An elevated level of ceramide can cause insulin resistance by inhibiting the ability of insulin to activate the insulin signal transduction pathway and/or via the activation of JNK.

Substances known to induce ceramide generation

• Anandamide
• Ceramidase inhibitors
• Chemotherapeutic agents
• Fas ligand
• Endotoxin
• Homocysteine
• Heat
• Hydroxypalmitoyl Sphinganine
• Gamma interferon
• Ionizing radiation
• Matrix metalloproteinases
• Niacinamide
• Reactive oxygen species
• Sphingosine
• Tetrahydrocannabinol and other cannabinoids{{Cite journal
• TNF-alpha
• 1,25 Dihydroxy vitamin D

Mechanism by which ceramide signaling occurs

Currently, the means by which ceramide acts as a signaling molecule are not clear.

One hypothesis is that ceramide generated in the plasma membrane enhances membrane rigidity and stabilizes smaller lipid platforms known as lipid rafts, allowing them to serve as platforms for signalling molecules. Moreover, as rafts on one leaflet of the membrane can induce localized changes in the other leaflet of the bilayer, they can potentially serve as the link between signals from outside the cell to signals to be generated within the cell.

Ceramide has also been shown to form organized large channels traversing the mitochondrial outer membrane. This leads to the egress of proteins from the intermembrane space.

Related diseases

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3, a massive altered composition of complex lipids occurs as a result of impaired mitochondrial fatty acid synthesis (mtFAS). For example, while the concentration of sphingomyelin is noticeably increased, the concentration of ceramides is proportionally decreased.

Uses

Ceramides may be found as ingredients of some topical skin medications used to complement treatment for skin conditions such as eczema. They are also used in cosmetic products such as some soaps, shampoos, skin creams, and sunscreens. Additionally, ceramides are being explored as a potential therapeutic in treating cancer.

Ceramide in bacteria

Ceramide is rarely found in bacteria. Bacteria of family Sphingomonadaceae, however, contain it.

Ceramide phosphoethanolamine

Ceramide phosphoethanolamine (CPE) is a sphingolipid consisted of a ceramide and a phosphoethanolamine head group. CPE is the major sphingolipid class in some invertebrates such as members of Drosophila. In contrast, mammalian cells contain only small amounts of CPE.

References

References

1. (2018-12-01). "Orm/ORMDL proteins: Gate guardians and master regulators". Advances in Biological Regulation.
2. Haimovitz-Friedman A. (1994). "Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis". J. Exp. Med..
3. (2008). "Principles of bioactive lipid signalling: lessons from sphingolipids". Nature Reviews Molecular Cell Biology.
4. (2008). "The sphingolipid salvage pathway in ceramide metabolism and signaling". Cell Signaling.
5. (2007). "Translational aspects of sphingolipid metabolism". Trends Mol. Med..
6. (2007). "Aging up-regulates expression of inflammatory mediators in mouse adipose tissue". The Journal of Immunology.
7. (2021). "Cholesterol - the devil you know; ceramide - the devil you don't". [[Trends (journals).
8. (2023). "Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease". [[International Journal of Biological Sciences]].
9. (2011). "Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice". [[Journal of Clinical Investigation]].
10. (2014). "Ceramides and glucosylceramides are independent antagonists of insulin signaling". Journal of Biological Chemistry.
11. (2005). "The effect of dietary sphingolipids on plasma sphingomyelin metabolism and atherosclerosis". [[Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids]].
12. (2014). "Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis". [[The American Journal of Pathology]].
13. (2014). "Ceramide and the mitochondrial respiratory chain". [[Biochimie]].
14. (1998). "p53-dependent ceramide response to genotoxic stress". J. Clin. Invest..
15. (2005). "Caspase-dependent and -independent activation of acid sphingomyelinase signaling". J. Biol. Chem..
16. (2001). "Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death". FEBS Letters.
17. (2006). "A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death". Biochimica et Biophysica Acta (BBA) - Biomembranes.
18. (22 August 2022). "Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes.". JCI Insight.
19. (2009). "Structures of the ceramides from porcine palatal stratum corneum". Lipids.
20. (2010). "The microstructure of the stratum corneum lipid barrier: mid-infrared spectroscopic studies of hydrated ceramide:palmitic acid:cholesterol model systems". [[Biophysical Chemistry]].
21. (2006). "Skin barrier". Taylor & Francis.
22. (2007). "Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis". [[Journal of Lipid Research]].
23. (8 September 1993). "Ceramide composition of the psoriatic scale.". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
24. (22 August 2022). "Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes". JCI Insight.
25. Coderch, Luisa, et al. "Ceramides and skin function." American journal of clinical dermatology 4 (2003): 107-129.
26. (2009). "Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome". [[American Journal of Physiology]].
27. Febbraio, Mark. (2014). "Role of interleukins in obesity:implications for metabolic disease". Trends in Endocrinology and Metabolism.
28. (2008). "Ceramide: a common pathway for atherosclerosis?". [[Atherosclerosis (journal).
29. (August 2014). "The Importance of Photoprotection and Moisturization in Treating Acne Vulgaris". Journal of Drugs in Dermatology.
30. "Hydroxypalmitoyl Sphinganine (Explained + Products)".
31. Hallahan DE. (1996). "Radiation-mediated gene expression in the pathogenesis of the clinical radiation response". Sem. Radiat. Oncol..
32. (2002). "Ceramide Channels Increase the Permeability of the Mitochondrial Outer Membrane to Small Proteins". J. Biol. Chem..
33. (2006). "Dihydroceramide hinders ceramide channel formation: Implications on apoptosis". Apoptosis.
34. (2006). "Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations". Mitochondrion.
35. (2019-11-01). "The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
36. Tucci, Sara. (2020-01-22). "Brain metabolism and neurological symptoms in combined malonic and methylmalonic aciduria". Orphanet Journal of Rare Diseases.
37. "Ceramides - Skin Lipids That Keep Skin Moisturized".
38. (May 16, 2014). "Safety Assessment of Ceramides as Used in Cosmetics". Cosmetic Ingredient Review.
39. (2011). "Apoptotic Sphingolipid Ceramide in Cancer Therapy". Journal of Lipids.
40. (2003). "Bacterial ceramides and sphingophospholipids induce apoptosis of human leukaemic cells". Microbiology.
41. (August 2007). "Molecular characterization of membrane-associated soluble serine palmitoyltransferases from Sphingobacterium multivorum and Bdellovibrio stolpii". Journal of Bacteriology.
42. (2005). "Bergey's manual of systematic bacteriology". Springer.