Detailed reviews of sphingolipid biosynthesis and metabolism have been . a high-fat diet (HFD) significantly increased plasma total ceramide levels .. The link between hypertension and ceramides suggests a novel. Phytoceramides are the plant-derived equivalent of ceramides, a lipid that keeps your skin hydrated and plump. Supplements with phytocermides are mostly. Find the answers to your top ceramide-related questions here. appearance firm and plump—especially given the recent research clarifying ceramides' sphingosine are ingredients known as ceramide precursors, meaning they can nudge.
Ceramide generation can also occur through breakdown of complex sphingolipids that are ultimately broken down into sphingosinewhich is then reused by reacylation to form ceramide.
This latter pathway is termed the Salvage pathway.
Sphingolipid - Wikipedia
Sphingomyelin hydrolysis[ edit ] 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.
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 dihydrosphingosinewhich 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.
Ceramide - Wikipedia
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. 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. 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. This increase in CerS1 expression was associated with alterations in ceramide levels and reduced glucose tolerance. Collectively these data demonstrate a complex interrelationship between sphingosine and ceramide metabolism and insulin resistance.
As pointed out ceramides can be deacetylated by ceramidases to form sphingosine. As discussed below, sphingosine can be phosphorylated to S1P which is an important biologically active lipid.
Ceramides can also be glucosylated by the enzyme, UDP-glucose ceramide glucosyltransferase also known as glucosylceramide synthase, GCSforming glucosylceramides which then serve as the building blocks of complex glycosphingolipids. Ceramides can also act as substrates for the sphingomyelin synthases yielding sphingomyelins or they can be phosphorylated by ceramide kinase to yield ceramidephosphate.
Thus, it is clear that multiple products of the actions of SPT, CerS, and DES1 could all potentially contribute to the development of insulin resistance and diabetes. As pointed out earleir, obesity is associated with a low-grade systemic inflammatory state.
One of the mechanisms involved in this inflammatory status is the activation of toll-like receptors TLRs. When TLRs are knocked-out in mice the animals are protected from lipid-induced insulin resistance.
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TLR4 activation has been shown to selectively and strongly increase the levels of sphingolipids within cells. Several studies have shown that ceramide is indeed an obligate intermediate linking TLR4 activation to the induction of insulin resistance.
Sphingolipid Metabolism and Obesity-Induced Inflammation
The four principal classes of glycosphingolipids are the cerebrosides, sulfatides, globosides and gangliosides. Cerebrosides have a single sugar group linked to ceramide. The most common of these is galactose galactocerebrosideswith a minor level of glucose glucocerebrosides.
Galactocerebrosides are found predominantly in neuronal cell membranes. By contrast glucocerebrosides are not normally found in membranes, especially neuronal membranes; instead, they represent intermediates in the synthesis or degradation of more complex glycosphingolipids.
Galactocerebrosides are synthesized from ceramide and UDP-galactose. Excess lysosomal accumulation of glucocerebrosides is observed in Gaucher disease. Glucocerebrosides are only intermediates in the synthesis of complex gangliosides or are found at elevated levels only in disease states such as Gaucher disease, where there is a defect in the catabolism of the complex gangliosides.
Thus, the presence of high concentrations of glucocerebrosides in cells such as monocytes and macrophages is indicative of a metabolic defect.
The sulfuric acid esters of galactocerebrosides are the sulfatides.