Ceramide 2442708 221761741 2008-06-25T23:55:58Z VolkovBot 3035831 robot Adding: [[sv:Ceramid]] [[Image:sphingolipid.png|thumb|375px|General chemical structure of [[sphingolipids]]. Different substituents (R) give: '''[[hydrogen|H]] - ceramide''', [[phosphocholine]] - [[sphingomyelin]], [[sugar]](s) - [[glycosphingolipid]](s).]] [[Image:Ceramid.svg|thumb|Ceramide]] '''Ceramides''' are a family of [[lipid]] molecules. A ceramide is composed of [[sphingosine]] and a [[fatty acid]]. Ceramides are found in high concentrations within the [[cell membrane]] of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the [[lipid bilayer]]. For years, it was assumed that ceramides and other [[sphingolipid]]s found in the bilayer cell membrane were purely structural elements. This is now known to be not completely true. Perhaps one of the most fascinating aspects of ceramide is that it can act as a [[lipid signaling|signaling]] molecule. The most well-known functions of ceramides as cellular signals include regulating the [[cell differentiation|differentiation]], [[cell proliferation|proliferation]], [[programmed cell death]] (PCD), and [[apoptosis]] (Type I PCD) of [[Cell (biology)|cell]]s. ==Pathways for ceramide synthesis== There are three major pathways of ceramide generation. The sphingomyelinase pathway uses an enzyme to breakdown sphingomyelin in the cell membrane and release ceramide. The de novo pathway creates ceramide from less complex molecules. Ceramide generation can also occur through breakdown of complex sphingolipids that are ultimately broken down into [[sphingosine]], which is then reused by reacylation to form ceramide. This latter pathway is termed the Salvage pathway. ===Sphingomyelin Hydrolysis=== [[Hydrolysis]] of [[sphingomyelin]] is catalyzed by the enzyme [[sphingomyelinase]]. Because [[sphingomyelin]] is one of the four common [[phospholipid]]s 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.<ref name="pmid8046331">{{cite journal |author=Haimovitz-Friedman A, Kan CC, Ehleiter D, ''et al'' |title=Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis |journal=J. Exp. Med. |volume=180 |issue=2 |pages=525–35 |year=1994 |pmid=8046331 |doi=}}</ref> ===De novo=== De novo synthesis of ceramide begins with the condesation 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]]. In the Golgi apparatus, ceramide can be further metabolized to other [[sphingolipids]], such as sphingomyelin and the glycosphingolipids.<ref name = "pmid18216770">{{cite journal |author=Hannun, Y.A. and Obeid, L.M. |title=Principles of bioactive lipid signalling: lessons from sphingolipids |journal=Nature Reviews: Molecular Cell Biology |volume=9 |pages=139–150 |year=2008 |pmid= 18216770 |doi=}}</ref> ===The Salvage Pathway=== Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the [[lysosomes]]. In case of glycosphingolipids, exohydrolases, acting at acidic pH optima, cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains one after the other leading to the generation of ceramide whereas sphingomyelin is converted to ceramide by acid [[sphingomyelinase]]. 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 in contrast to 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]] [20]. 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. It should also be noted that the salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis <ref name = "pmid18191382">{{cite journal |author=Kitatani, K., Idkowiak-Baldys, J., and Hannun, Y.A. |title=The sphingolipid salvage pathway in ceramide metabolism and signaling. |journal=Cell Signaling |volume=30 |issue=6 |pages=1010–1018 |year=2008 |pmid= 18191382 |doi=}}</ref> ==Physiological Roles of Ceramide== 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. <ref name = "pmid18216770">{{cite journal |author=Hannun, Y.A. and Obeid, L.M. |title=Principles of bioactive lipid signalling: lessons from sphingolipids |journal=Nature Reviews: Molecular Cell Biology |volume=9 |pages=139–150 |year=2008 |pmid= 18216770 |doi=}}</ref> 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]]. <ref name = "pmid17588815">{{cite journal |author=Zeidan, Y.H., and Hannun, Y.A. |title=Translational aspects of sphingolipid metabolism. |journal=Trends Mol. Med. |volume=13 |issue=8 |pages=327–336 |year=2007 |pmid=17588815 |doi=}}</ref> ===Apoptosis=== One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. [[Apoptosis]], a form of [[programmed cell death]], is essential for the maintenace 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 <ref name="pmid8046331">{{cite journal |author=Haimovitz-Friedman A, Kan CC, Ehleiter D, ''et al'' |title=Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis |journal=J. Exp. Med. |volume=180 |issue=2 |pages=525–35 |year=1994 |pmid=8046331 |doi=}}</ref><ref name = "pmid9664074">{{cite journal |author=Dbaibo, G.S., Pushkareva, M.Y., Rachid, R.A., Alter, N., Smyth, M.J., Obeid, L.M., and Hannun, Y.A. |title=p53-dependent ceramide response to genotoxic stress. |journal=J. Clin. Invest. |volume=102|issue=2 |pages=329–339 |year=1998 |pmid=9664074 |doi=}}</ref>, [[UV]] light <ref name="pmid15849201">{{cite journal |author=Rotolo, J.A., Zhang, J., Donipui, M., Lee, H., Fuks, Z., and Kolesnick, R.N. |title=Caspase-dependent and -independent activation of acid sphingomyelinase signaling. |journal=J. Biol. Chem. |volume=280 |issue=28 |pages=26425–34 |year=2005 |pmid=15849201 |doi=}}</ref>, [[TNF-alpha]] <ref name = "pmid11513845">{{cite journal |author=Dbaibo, G.S., El-Assad, W., Krikorian, A., Liu, B., Diab, K., Idriss, N.Z., El-Sabban, M., Driscoll, T.A., Perry, D.K., and Hannun, Y.A. |title=Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death. |journal=FEBS Letters |volume=503 |pages=7–12 |year=2001 |pmid=11513845 |doi=}}</ref>, and [[chemotherapy|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. <ref name = "pmid17161984">{{cite journal |author=Taha, T.A., Mullen, T.D. and Obeid, L.M. |title=A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. |journal=Biochim. Biophys. Acta |volume=1758 |issue=12 |pages=2027–36 |year=2006 |pmid=17161984 |doi=}}</ref>. ==Substances known to induce ceramide generation== *[[TNF-alpha]] *[[Endotoxin]] *[[chemotherapy|Chemotherapeutic agents]] *[[vitamin D|1,25 dihydroxy vitamin D]] *[[interferon|gamma interferon]] *heat *[[ionizing radiation]] <ref name="pmid8046331" /><ref>{{cite journal |author=Hallahan DE |title=Radiation-mediated gene expression in the pathogenesis of the clinical radiation response |journal=Sem. Radiat. Oncol. |volume=6 |issue=4 |pages=250–267 |year=1996 |pmid=10717183 |doi=10.1016/S1053-4296(96)80021-X}}</ref> *Ceramidase Inhibitors It is interesting to note that the substances that can cause ceramide to be generated tend to be stress signals that can cause the cells to go into programmed cell death. Ceramide thus acts as an intermediary signal that connects the external signal to the internal metabolism of the cells. ==Mechanism by which ceramide signalling 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]] stabilizes smaller lipid platforms known as [[lipid rafts]], allowing them to serve as platforms for signalling molecules. Moreover, as rafts can cross the entire lipid bilayer, they can serve as the link between signals outside of 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. <ref>{{cite journal |author=Siskind LJ, Kolesnick RN, Colombini M |title=Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins |journal=J. Biol. Chem. |volume=277 |issue=30 |pages=26796–803 |year=2002 |pmid=12006562 |doi=10.1074/jbc.M200754200}}</ref><ref>{{cite journal |author=Stiban J, Fistere D, Colombini M |title=Dihydroceramide hinders ceramide channel formation: Implications on apoptosis |journal=Apoptosis |volume=11 |issue=5 |pages=773–80 |year=2006 |pmid=16532372 |doi=10.1007/s10495-006-5882-8}}</ref><ref>{{cite journal |author=Siskind LJ, Kolesnick RN, Colombini M |title=Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations |journal=Mitochondrion |volume=6 |issue=3 |pages=118–25 |year=2006 |pmid=16713754 |doi=10.1016/j.mito.2006.03.002}}</ref> ==References== <references/> ==External links== * {{MeshName|Ceramides}} {{Sphingolipids}} [[Category:Lipids]] [[de:Ceramide]] [[es:Ceramida]] [[fr:Céramide]] [[it:Ceramide]] [[ja:セラミド]] [[pl:Ceramidy]] [[pt:Ceramida]] [[ru:Церамид]] [[sv:Ceramid]]