Phosphorylation of sphingosine derived from ceramide stimulates pro-life metabolic pathways and acts to .. the large number of capsules required at higher doses, However, the relationship between 4-HPR plasma levels. has a chemical-class profile for Ceramide. Ceramides at the US National Library of Medicine Medical Subject Headings (MeSH). in the cytotoxicity of 4-HPR, cells were treated with the sphingosine kinase inhibitor cancer cells but also the relationship between ceramide metabolism and levels ranged from to Amol/L (4-HPR capsules,. mg/m2 twice.
Ceramides can serve as the substrates for sphingosine synthesis and sphingosine can serve as a substrate for ceramide synthesis, as depicted, through the actions of ceramidases and ceramide synthases. Sphingomyelins are important structural lipid components of nerve cell membranes. The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine. Sphingomyelins represent a class of lipid and the N-acylated fatty acid can be of varying lengths as well as being unsaturated.
The sphingomyelin depicted contains the carbon saturated fatty acid, stearic acid. The sphingomyelins are synthesized by the transfer of phosphorylcholine from phosphatidylcholine to a ceramide in a reaction catalyzed by sphingomyelin synthases SMS. Expression of the SGMS1 gene predominates in the brain. The SMS2 enzyme is encoded by the SGMS2 gene located on chromosome 4q25 which is composed of 11 exons that generate three alternatively spliced mRNAs, all of which encode the same amino acid protein.
Metabolism of the sphingomyelins. The interconversion of ceramides and sphoingomyelins occurs as a result of the actions of sphingomyelinases and sphingomyelin synthases. The fatty acid incorporated into a ceramide by sphingomyelin synthases is most commonly derived from a phosphatidylcholine, PC.
As shown in the Figure above, sphingomyelins are degraded via the action of sphingomyelinases resulting in release of ceramides and phosphocholine. The sphingomyelinase in humans functions at acidic pH and is, therefore, referred to as acid sphingomyelinase ASMase or aSMase. The human ASMase is encoded for by the sphingomyelin phosphodiesterase-1 gene gene symbol: SMPD1 which is located on chromosome 11p There are in fact two major forms of Niemann-Pick NP disease.
With respect to the sphingomyelins they serve a dual purpose of being important membrane phospholipids and as a reservoir for ceramides. The conversion of both dihydrosphingosine sphinganine and sphingosine to ceramide is catalyzed by the ceramide synthases CerS.
CerS were originally referred to as Lass genes for Longevity Assurance based on their homology to the yeast gene, longevity assurance gene-1 LAG1. LAG1 was so-called because deletion of the gene in yeast prolonged their life-span.
An additional related gene in yeast is referred to as LAC1 and when both genes are deleted yeast exhibit poor growth or die.
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A human gene, originally identified as UOG-1 upstream of growth and differentiation factor-1was shown to complement a LAG1 deletion in yeast and when overexpressed in mammalian cells resulted in increased ceramide synthesis.
The ceramides synthesized by the enzyme contained exclusively stearic acid C18 saturated fatty acid. Subsequent studies demonstrated that other human LAG homologs, originally identified as translocating chain-associating membrane proteins TRH synthesized ceramides with varying fatty acyl chain length.
Each of these genes are now identified as CerS. Each CerS exhibits fatty acyl chain length specificity as well as differential tissue distribution.
CerS1 is specific for stearic acid C18 and is expressed in brain, skeletal muscle, and testis. CerS2 is specific for C20—C26 fatty acids and is expressed in the liver and kidney. CerS3 is specific for C22—C26 fatty acids and is expressed in the skin and testis. CerS4 is specific for C18—C20 fatty acids and is ubiquitously expressed but with highest levels in liver, heart, skin, and leukocytes. CerS5 is specific for palmitic acid C16 and is ubiquitously expressed at low levels.
CerS6 is specific for myristic C14 and palmitic acid and is expressed at low levels in all tissues. CerS1 is structurally and functionally distinct from the other five CerS all, of which contain a homeobox-like domain. The CERS1 gene is located on chromosome19p Transcription of the isoform 3 amino acids encoding mRNA begins from an alternative promoter than the other two mRNAs. The CERS2 gene is located on chromosome 1q The CERS3 gene is located on chromosome 15q The CERS4 gene is located on chromosome 19p The CERS5 gene is located on chromosome 12q The CERS6 gene is located on chromosome 2q The biological significance of ceramide synthesis and the activity of the CerS is demonstrated by studies in several different types of human cancers.
In this regard CerS1 appears to most significant. Head and neck squamous cell carcinomas HNSCC exhibit a downregulation of Cceramide levels when compared to adjacent normal tissue. In the chemotherapy of certain cancers, CerS1 activity may also play a role.
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Enhanced expression of CerS1 has been shown to sensitize cells to a variety of chemotherapeutic drugs such as cisplatin, vincristine, and doxorubicin.
The proposed mechanism for ceramide involvement in apoptotic processes involves the activation of the aspartate protease cathepsin D. Cathepsin D is associated with membranes and when activated by ceramides is released to the cytosol where it triggers the mitochondrial apoptosis pathway. Further evidence for the role of ceramides in negative growth responses is seen in cell cultures to which ceramide analogues are added.
When derived from the sphingomyelins, ceramides are the products of the action of acid sphingomyelinase ASMase. The importance of sphingomyelin as a source of ceramide can be evidenced by the fact that the activation of the ASMase pathway is a shared response to the effects of cytokines, stress, radiation, chemotherapeutic drugs, and pathogenic and cytotoxic agents. The induction of ASMase, in response to apoptotic triggers, results in increased production of ceramides which then can initiate aspects of the apoptosis pathways as described above.
In addition, there is ample evidence demonstrating that the accumulation of cellular ceramides is associated with the pathogenesis of diseases such as obesitydiabetesatherosclerosis, and cardiomyopathy. For example, studies in mice have correlated endogenous ceramides and glucosylceramides with the antagonism of insulin-stimulated glucose uptake and synthesis.
An enhanced systemic inflammatory status as well as cellular stress have both been associated with insulin resistance. With respect to biological lipids, excess lipid intake, especially saturated fatty acids, leads to mitochondrial and endoplasmic reticulum ER stress. Increased fat oxidation in mitochondria leads to the production of reactive oxygen species ROS which are known to result in insulin resistance.
Both mitochondrial and ER stress can result in apoptosis. Excess fatty acid intake also interferes with normal insulin receptor-mediated signal transduction resulting in insulin resistance. For more information on the role of fats and mitochondrial stress in insulin resistance visit the Insulin Functions page.
Obesitywhich results in insulin resistance and development of type 2 diabetes, has long been associated with low-grade systemic inflammation. The correlation between obesity, ceramide synthesis, and insulin resistance is discussed below. Experiments in cell culture, involving both adipocytes and skeletal muscle cells, have shown that ceramides inhibit insulin-stimulated glucose uptake by blocking translocation of GLUT4 to the plasma membrane as well as by interfering with glycogen synthesis.
The phosphorylation leads to reduced affinity of the kinase for phosphoinositides. The role of saturated fatty acids in increased levels of ceramides has been demonstrated by adding palmitate to cultured muscle cells. An alternative means to examine the effects of ceramides on insulin sensitivity is to block the pathways of ceramide metabolism. Under conditions of ceramidase inhibition there is an exagerated effect of palmitic acid addition on insulin resistance. Conversely, if one overexpresses acid ceramidase, the inhibition of insulin signaling induced by palmitate addition is completely blocked.
The cellular effects of glucosylceramide, although similar to ceramides themselves, does exhibit cell-type specificity. Glucosylceramide is the precursor for a complex family of gangliosides, for example the GM3 ganglioside.
Adipocytes are highly sensitive to the inhibitory effects of glucosylated sphingolipids on insulin actions, whereas muscle cells are unaffected. The significance of the accumulation of these gangliosides has been demonstrated in mice lacking GM3 synthase which generates the major ganglioside precursor. These mice are protected from insulin resistance and glucose intolerance when fed a high-fat diet. Treatment of genetically obese or diet-induced obese mice with highly specific glucosylceramide synthase UDP-glucose ceramide glucosyltransferase, UGCG inhibitors results in improved glucose tolerance and increased insulin sensitivity in muscle and liver.
Collectively, these studies strongly implicate a role for glucosylated ceramides in increased adipose tissue inflammation, peripheral insulin resistance, and hepatic steatosis. The most potent reagent used to study the effects of the manipulation of enzymes involved in sphingolipid biosynthesis is the compound myriocin [2-Amino-3,4-dihydroxy hydroxymethyl oxoicosenoic acid].
Myriocin is a highly specific inhibitor of serine palmitoyltransferase SPTwhich is the first and rate-limiting enzyme in the de novo pathway of ceramide synthesis.
See the Figure above showing sphingosine and ceramide synthesis. Myriocin also known as antibiotic ISP-1 and thermozymocidin was isolated from themophilic fungi such as Mycelia sterilia and Isaria sinclairii. Extracts from these fungi have been used in traditional Chinese medicine as a treatment for numerous conditions including diabetes. Myriocin can be administered chronically to rodents and it appears to be well tolerated.
Addition of myriocin to animals that are models of obesity prevents insulin resistance and the development of diabetes, atherosclerosis, and cardiomyopathy.
In addition, myriocin improved glucose tolerance, insulin sensitivity and ameliorates hypertension when administered to rodents. Genetic manipulation of several enzymes in ceramide metabolism has also been shown to insulin sensitizing. In mice heterozygous for the SPT subunit SPTLC2 there is a reduction in peripheral ceramide levels and improved insulin sensitivity when these animals are fed a high-fat diet.
Similar results are seen in mice heterozygous for dihydroceramide desaturase 1 DES1. As described above, a large family of ceramide synthases CerS have been identified in mammals. CerS1 is the most abundant isoform expressed in skeletal muscle and is involved primarily in the synthesis of C The level of expression of CerS1 was shown to be significantly elevated in mice fed a high-fat diet.
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 sphingolipidssuch as sphingomyelin and the complex glycosphingolipids.
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 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.
Apoptosisor Type I programmed cell deathis 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.