Ceramide
Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation, proliferation, and programmed cell death of cells.
The word ceramide comes from the Latin cera and amide. Ceramide is a component of vernix caseosa, the waxy or cheese-like white substance found coating the skin of newborn human infants.
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
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 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
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.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. 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
Ceramide is the main component of the stratum corneum of the epidermis layer of human skin. Together with cholesterol and saturated fatty acids, ceramide creates a water-impermeable, protective organ to prevent excessive water loss due to evaporation as well as a barrier against the entry of microorganisms. In the hyperplastic disorder psoriasis the water permeability barrier is compromised. Ceramide VI is the most abundant ceramide of the skin, along with ceramide II, and has been exploited to model the organization of the stratum corneum lipidic network.The stratum corneum is composed of 50% ceramides, 25% cholesterol, and 15% free fatty acids. Key components of the extracellular lipid lamellae of the stratum corneum are ultra long chain ceramides. With aging there is a decline in ceramide and cholesterol in the stratum corneum of humans. A clinical trial using ceramide-rich wheat extract showed increased skin hydration in those taking the extract rather than the placebo.
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
- Gamma interferon
- Ionizing radiation
- Matrix metalloproteinases
- Niacinamide
- Reactive oxygen species
- Tetrahydrocannabinol and other cannabinoids
- TNF-alpha
- 1,25 Dihydroxy vitamin D
Mechanism by which ceramide signaling occurs
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.