Journal articles: 'Ceramidase'

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Yuan, Changqing, Raghavendra Pralhada Rao, Nahid Jesmin, Takeshi Bamba, Kunio Nagashima, Alberto Pascual, Thomas Preat, Eiichiro Fukusaki, Usha Acharya, and Jairaj K. Acharya. "CDase is a pan-ceramidase in Drosophila." Molecular Biology of the Cell 22, no. 1 (January 2011): 33–43. http://dx.doi.org/10.1091/mbc.e10-05-0453.

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Ceramidases catalyze the conversion of ceramide to sphingosine. They are acylaminohydrolases that catalyze the deacylation of the amide-linked saturated fatty acid from ceramide to generate sphingosine. They also catalyze the reverse reaction of ceramide biosynthesis using sphingosine and fatty acid. In mammals, different proteins catalyze these reactions while individually exhibiting optimal activity over a narrow pH range and have been accordingly called acid, neutral, and alkaline ceramidases. Several genes encode for variants of alkaline ceramidase in mammals. Brainwashing (Bwa) is the only putative alkaline ceramidase homologue present in Drosophila. In this study we have demonstrated that BWA does not exhibit ceramidase activity and that bwa null mutants display no loss of ceramidase activity. Instead, the neutral ceramidase gene CDase encodes the protein that is responsible for all measurable ceramidase activity in Drosophila. Our studies show strong genetic interaction of Bwa with CDase and the Drosophila ceramide kinase gene (DCERK). We show that, although BWA is unlikely to be a ceramidase, it is a regulator of sphingolipid flux in Drosophila. Bwa exhibits strong genetic interaction with other genes coding for ceramide-metabolizing enzymes. This interaction might partly explain its original identification as a ceramidase.

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Duarte, Carolina, Juliet Akkaoui, Chiaki Yamada, Anny Ho, Cungui Mao, and Alexandru Movila. "Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration." Cells 9, no. 6 (June 2, 2020): 1379. http://dx.doi.org/10.3390/cells9061379.

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Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.

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Parveen, Farzana, Daniel Bender, Shi-Hui Law, Vineet Kumar Mishra, Chih-Chieh Chen, and Liang-Yin Ke. "Role of Ceramidases in Sphingolipid Metabolism and Human Diseases." Cells 8, no. 12 (December 4, 2019): 1573. http://dx.doi.org/10.3390/cells8121573.

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Human pathologies such as Alzheimer’s disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3—which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.

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Jin, K., Y. Higaki, Y. Takagi, K. Higuchi, Y. Yada, M. Kawashima, and G. Imokawa. "Analysis of beta-glucocerebrosidase and ceramidase activities in atopic and aged dry skin." Acta Dermato-Venereologica 74, no. 5 (September 1, 1994): 337–40. http://dx.doi.org/10.2340/0001555574341343.

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To elucidate the mechanisms that are involved in the decrease of ceramide levels in atopic dry skin and in aged skin, we examined both the activities of beta-glucocerebrosidase, which is a major enzyme in ceramide production, and of ceramidase, which is an essential enzyme in ceramide degradation, in the stratum corneum of atopic dry skin and aged skin. The specimens of the stratum corneum of forearm skin were obtained by tape-stripping from 61 healthy volunteers and 23 patients with atopic uninvolved skin. The beta-glucocerebrosidase activity in the stratum corneum extracts was estimated using fluorescent 4-methylumbelliferyl-beta-D-glucopyranoside as the substrate. Ceramidase activity was determined using 14C-palmitoylsphingosine as the substrate. Among the atopic skin samples, neither beta-glucocerebrosidase nor ceramidase activities were different from those of age-matched healthy controls. Nor was the beta-glucocerebrosidase activity deficient in the aged skin samples as compared to that seen in samples from the young, healthy group. In contrast, there was an age-related upregulation in ceramidase activity. The results indicate that the decrease of ceramides in atopic dry skin may not be accompanied by reduced synthesis or by enhanced degradation, each of which is primarily attributable to the above two enzymes, respectively. The pathogenesis of aged dry skin can be explained, at least partially, in terms of elevated ceramidase activity, which results in a disturbance of the lamellar structure of the stratum corneum lipids.

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Ramachandra, Nagaraju, and Andreas Conzelmann. "Membrane topology of yeast alkaline ceramidase YPC1." Biochemical Journal 452, no. 3 (May 31, 2013): 585–94. http://dx.doi.org/10.1042/bj20130085.

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Ypc1p (yeast phyto-ceramidase 1) and Ydc1p (yeast dihydroceramidase 1) are alkaline ceramide hydrolases that reside in the ER (endoplasmic reticulum). Ypc1p can catalyse the reverse reaction, i.e. the condensation of non-esterified fatty acids with phytosphingosine or dihydrosphingosine and overexpression of YPC1 or YDC1 can provide enough ceramide synthesis to rescue the viability of cells lacking the normal acyl-CoA-dependent ceramide synthases. To better understand the coexistence of acyl-CoA-dependent ceramide synthases and ceramidases in the ER we investigated the membrane topology of Ypc1p by probing the cysteine residue accessibility of natural and substituted cysteines with membrane non-permeating mass-tagged probes. The N- and C-terminal ends of Ypc1p are oriented towards the lumen and cytosol respectively. Two of the five natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. The data allow the inference that all of the amino acids of Ypc1p that are conserved in the Pfam PF05875 ceramidase motif and the CREST {alkaline ceramidase, PAQR [progestin and adipoQ (adiponectin) receptor] receptor, Per1 (protein processing in the ER 1), SID-1 (sister disjunction 1) and TMEM8 (transmembrane protein 8)} superfamily are located in or near the ER lumen. Microsomal assays using a lysine residue-specific reagent show that the reverse ceramidase activity can only be blocked when the reagent has access to Ypc1p from the lumenal side. Overall the data suggest that the active site of Ypc1p resides at the lumenal side of the ER membrane.

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Zaibaq, Faris, Tyrone Dowdy, and Mioara Larion. "TMET-36. ACID CERAMIDASE INHIBITION EXPLOITS SPHINGOLIPID VULNERABILITIES IN IDH MUTANT GLIOMAS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii269—vii270. http://dx.doi.org/10.1093/neuonc/noac209.1041.

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Abstract The presence of the IDH mutation in gliomas is a major classifier of brain tumor subtypes and has several important implications for cancer growth. Our recent work uncovered that IDH-mutant tumors are susceptible to increased apoptosis via alterations of the sphingolipid pathway due to their excess production of pro-apoptotic ceramides over pro-proliferative sphingosine 1-phosphate (S1P). To that end, we proposed that this rheostat can be modulated to induce cell death in IDHmut tumors by targeting acid ceramidase, a critical sphingolipid enzyme in gliomas. We hypothesize that pharmacological inhibition of acid ceramidase will increase ceramide levels and therefore induce apoptosis in IDHmutgliomas. Using a preliminary drug screen, we have identified a group of haloacetate C2-ceramide derivatives known as SOBRACs that potently inhibit acid ceramidase. We selected five candidate compounds from this family and assessed the effectiveness of each drug in 3 I IDHmut (BT142, TS603, & U251mut) and 3 IDHmut (GSC923, GSC827, U251wt) patient-derived glioma cell lines, as well as non-immortalized normal human astrocytes, using the CCK8 cell viability assay. Our results indicate that the SOBRAC drugs are nearly 10 times more potent in IDH-mutant tumors compared to IDHmut cell lines. Additionally, the SOBRAC drugs are more effective than other known acid ceramidase inhibitors, making them attractive as potential novel therapeutics. To date, azide-SOBRAC is the most potent drug in the family, with EC50 value of 300 nM in BT142 cells (IDHmutmut

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Proksch, Denny, Jan Jasper Klein, and Christoph Arenz. "Potent Inhibition of Acid Ceramidase by Novel B-13 Analogues." Journal of Lipids 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/971618.

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The lipid-signalling molecule ceramide is known to induce apoptosis in a variety of cell types. Inhibition of the lysosomal acid ceramidase can increase cellular ceramide levels and thus induce apoptosis. Indeed, inhibitors of acid ceramidase have been reported to induce cell death and to display potentiating effects to classical radio- or chemo therapy in a number ofin vitroandin vivocancer models. The most potentin vitroinhibitor of acid ceramidase, B-13, recently revealed to be virtually inactive towards lysosomal acid ceramidase in living cells. In contrast, a number of weakly basic B-13 analogues have been shown to accumulate in the acidic compartments of living cells and to efficiently inhibit lysosomal acid ceramidase. However, introduction of weakly basic groups at theω-position of the fatty acid moiety of B-13 led to a significant reduction of potency towards acid ceramidase from cellular extracts. Herein, we report a novel B-13-derived scaffold for more effective inhibitors of acid ceramidase. Furthermore, we provide hints for an introduction of basic functional groups at an alternative site of the B-13 scaffold that do not interfere with acid ceramidase inhibitionin vitro.

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Yi, Jae Kyo, Ruijuan Xu, Lina M. Obeid, Yusuf A. Hannun, Michael V. Airola, and Cungui Mao. "Alkaline ceramidase catalyzes the hydrolysis of ceramides via a catalytic mechanism shared by Zn2+-dependent amidases." PLOS ONE 17, no. 9 (September 1, 2022): e0271540. http://dx.doi.org/10.1371/journal.pone.0271540.

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Human alkaline ceramidase 3 (ACER3) is one of three alkaline ceramidases (ACERs) that catalyze the conversion of ceramide to sphingosine. ACERs are members of the CREST superfamily of integral-membrane hydrolases. All CREST members conserve a set of three Histidine, one Aspartate, and one Serine residue. Although the structure of ACER3 was recently reported, catalytic roles for these residues have not been biochemically tested. Here, we use ACER3 as a prototype enzyme to gain insight into this unique class of enzymes. Recombinant ACER3 was expressed in yeast mutant cells that lack endogenous ceramidase activity, and microsomes were used for biochemical characterization. Six-point mutants of the conserved CREST motif were developed that form a Zn-binding active site based on a recent crystal structure of human ACER3. Five point mutants completely lost their activity, with the exception of S77A, which showed a 600-fold decrease compared with the wild-type enzyme. The activity of S77C mutant was pH sensitive, with neutral pH partially recovering ACER3 activity. This suggested a role for S77 in stabilizing the oxyanion of the transition state. Together, these data indicate that ACER3 is a Zn2+-dependent amidase that catalyzes hydrolysis of ceramides via a similar mechanism to other soluble Zn-based amidases. Consistent with this notion, ACER3 was specifically inhibited by trichostatin A, a strong zinc chelator.

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Olsson, Maria, Rui-Dong Duan, Lena Ohlsson, and Åke Nilsson. "Rat intestinal ceramidase: purification, properties, and physiological relevance." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 4 (October 2004): G929—G937. http://dx.doi.org/10.1152/ajpgi.00155.2004.

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Neutral ceramidase activity has previously been identified in the intestinal mucosa and gut lumen and postulated to be important in the digestion of sphingolipids. It is found throughout the intestine but has never been fully characterized. We have purified rat intestinal neutral ceramidase from an eluate obtained by perfusing the intestinal lumen with 0.9% NaCl and 3 mM sodium taurodeoxycholate. Using a combination of acetone precipitation and ion-exchange, hydrophobic-interaction, and gel chromatographies, we obtained a homogenous enzyme protein with a molecular mass of ∼116 kDa. The enzyme acts on both [14C]octanoyl- and [14C]palmitoyl-sphingosine in the presence of glycocholic and taurocholic acid and the bile salt analog 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate but is inhibited by 2 mM or more of other bile salts. It is a glycosylated protein stable to trypsin and chymotrypsin exposure, is not influenced by Ca2+, Mg2+, or Mn2+, and is inhibited by Zn2+ and Cu2+. Mass fragmentographic analysis identified 12 fragments covering 17.5% of the sequence for neutral/alkaline ceramidase 2 purified (Mitsutake S, Tani M, Okino N, Mori K, Ichinose S, Omori A, Iida H, Nakamura T, and Ito M. J Biol Chem 276: 26249–262459, 2001) from rat kidney and located in apical membrane of renal tubular cells. Intestinal and kidney ceramidases also have similar molecular mass and ion dependence. Intestinal ceramidase thus is a neutral ceramidase 2 released by bile salts and resistant to pancreatic proteases. It is well suited to metabolize ceramide formed from dietary and brush border sphingolipids to generate other bioactive sphingolipid messengers.

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BIONDA, Clara, Jacques PORTOUKALIAN, Daniel SCHMITT, Claire RODRIGUEZ-LAFRASSE, and Dominique ARDAIL. "Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria?" Biochemical Journal 382, no. 2 (August 24, 2004): 527–33. http://dx.doi.org/10.1042/bj20031819.

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Recent studies by our group and others have disclosed the presence of ceramides in mitochondria, and the activities of ceramide synthase and reverse ceramidase in mitochondria have also been reported. Since a possible contamination with the ER (endoplasmic reticulum)-related compartment MAM (mitochondria-associated membrane) could not be ruled out in previous studies, we have re-investigated the presence of the enzymes of ceramide metabolism in mitochondria and MAM highly purified from rat liver. In the present paper, we show that purified mitochondria as well as MAM are indeed able to generate ceramide in vitro through both ceramide synthase or reverse ceramidase, whereas the latter enzyme activity is barely detectable in microsomes. Moreover, ceramide synthase activities were recovered in outer mitochondrial membranes as well as in inner mitochondrial membranes. Using radiolabelled sphingosine as a substrate, mitochondria could generate ceramide and phytoceramide. However, the in vitro sensitivity of ceramide synthase toward FB1 (fumonisin B1) in mitochondria as well as in MAM was found to depend upon the sphingoid base: whereas dihydrosphingosine N-acyltransferase was inhibited by FB1 in a concentration-dependent manner, FB1 actually activated the ceramide synthase when using sphingosine as a substrate. Acylation of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate, generating ceramide 1-phosphate, was also shown with both subcellular fractions. Moreover, the same difference in sensitivity towards FB1 for the ceramide synthase activities was seen between the two phosphorylated sphingoid bases, raising the possibility that distinct base-specific enzymes may be involved as ceramide synthases. Collectively, these results demonstrate the involvement of mitochondria in the metabolism of ceramides through different pathways, thereby supporting the hypothesis that topology of ceramide formation could determine its function.

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Beckmann, Nadine, Katrin Anne Becker, Stephanie Kadow, Fabian Schumacher, Melanie Kramer, Claudine Kühn, Walter J. Schulz-Schaeffer, et al. "Acid Sphingomyelinase Deficiency Ameliorates Farber Disease." International Journal of Molecular Sciences 20, no. 24 (December 11, 2019): 6253. http://dx.doi.org/10.3390/ijms20246253.

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Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.

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Li, Wen-hong. "Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes." Molecules 27, no. 18 (September 19, 2022): 6117. http://dx.doi.org/10.3390/molecules27186117.

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Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and mitochondrial dysfunction. Studies over the last few decades have highlighted the role played by ceramides in pancreatic islet β-cell apoptosis, especially under glucolipotoxic and inflammatory conditions. This review focuses on ceramides and adiponectin receptor signaling, summarizing recent advancements in our understanding of their roles in islet β-cells and the discovery of zinc-dependent lipid hydrolase (ceramidase) activity of adiponectin receptors. The therapeutic potential of targeting these events to prevent islet β-cell loss for treating diabetes is discussed.

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Zager, R. A., D. S. Conrad, and K. Burkhart. "Ceramide accumulation during oxidant renal tubular injury: mechanisms and potential consequences." Journal of the American Society of Nephrology 9, no. 9 (September 1998): 1670–80. http://dx.doi.org/10.1681/asn.v991670.

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Ceramide is an important signaling molecule that is typically generated via sphingomyelinase (SMase)-mediated sphingomyelin (SM) hydrolysis. Although diverse forms of renal injury elicit ceramide accumulation, the molecular determinants of this change and its contribution to tissue damage are poorly defined. The present study uses iron (Fe/hydroxyquinoline)-mediated injury of cultured human proximal tubular (HK-2) cells to gain additional insights into these issues. A 4-h Fe exposure doubled ceramide levels in the absence of cell death. This was independent of de novo synthesis, since ceramide synthase inhibition (with fumonisin B1) had no effect. Oxidant stress directly suppressed, rather than stimulated, SMase activity by: (1) decreasing SMase levels; (2) depleting SMase-stimulating glutathione; and (3) increasing SM resistance to SMase attack. Fe suppressed cell sphingosine levels (3 to 4 times ceramide/sphingosine ratio increments), suggesting a possible ceramidase block. Fe did not directly affect HK-2 ceramidase levels. However, arachidonic acid (C20:4) accumulation, a consequence of oxidant-induced phospholipase A2 (PLA2) activation, markedly suppressed ceramidase and stimulated SMase activity. Exogenous C20:4, as well as PLA2 (in doses simulating Fe-induced deacylation) recapitulated Fe's ceramide-generating effect. Because C20:4 is directly cytotoxic, it was hypothesized that ceramide might offset some of C20:4's adverse effects. Supporting this possibility were the following: (1) C20:4 exacerbated Fe toxicity; (2) this was abrogated by ceramide treatment; and (3) ceramide blunted Fe-mediated cell death. Conclusions: (1) ceramide accumulation during acute cell injury can be an adaptive response to PLA2 activation/C20:4 generation; (2) C20:4-induced ceramidase inhibition, coupled with SMase stimulation, may trigger this result; and (3) these ceramide increments may exert a "biostat" function, helping to offset C20:4/PLA2- and "catalytic" iron-mediated tubular cell death.

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Vijayan, Yadu, Manendra Babu Lankadasari, and Kuzhuvelil B. Harikumar. "Acid Ceramidase: A Novel Therapeutic Target in Cancer." Current Topics in Medicinal Chemistry 19, no. 17 (September 19, 2019): 1512–20. http://dx.doi.org/10.2174/1568026619666190227222930.

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Sphingolipids are important constituents of the eukaryotic cell membrane which govern various signaling pathways related to different aspects of cell survival. Ceramide and Sphingosine are interconvertible sphingolipid metabolites, out of which Ceramide is pro-apoptotic and sphingosine is anti-apoptotic in nature. The conversion of ceramide to sphingosine is mediated by Acid Ceramidase (ASAH1) thus maintaining a rheostat between a tumor suppressor and a tumor promoter. This rheostat is completely altered in many tumors leading to uncontrolled proliferation. This intriguing property of ASAH1 can be used by cancer cells to their advantage, by increasing the expression of the tumor promoter, sphingosine inside cells, thus creating a favorable environment for cancer growth. The different possibilities through which this enzyme serves its role in formation, progression and resistance of different types of cancers will lead to the possibility of making Acid Ceramidase a promising drug target. This review discusses the current understanding of the role of acid ceramidase in cancer progression, metastasis and resistance, strategies to develop novel natural and synthetic inhibitors of ASAH1 and their usefulness in cancer therapy.

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Geiger, Nina, Louise Kersting, Jan Schlegel, Linda Stelz, Sofie Fähr, Viktoria Diesendorf, Valeria Roll, et al. "The Acid Ceramidase Is a SARS-CoV-2 Host Factor." Cells 11, no. 16 (August 15, 2022): 2532. http://dx.doi.org/10.3390/cells11162532.

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SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.

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Beckmann, Nadine, Stephanie Kadow, Fabian Schumacher, Joachim R. Göthert, Stefanie Kesper, Annette Draeger, Walter J. Schulz-Schaeffer, et al. "Pathological manifestations of Farber disease in a new mouse model." Biological Chemistry 399, no. 10 (September 25, 2018): 1183–202. http://dx.doi.org/10.1515/hsz-2018-0170.

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Abstract Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

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Hawkins, Cyntanna C., Amber B. Jones, Emily R. Gordon, Sarah E. Williford, Yuvika Harsh, Julia K. Ziebro, Catherine J. Landis, et al. "Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling." Cells 11, no. 12 (June 9, 2022): 1873. http://dx.doi.org/10.3390/cells11121873.

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Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.

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Ouairy, Cécile M. J., Maria J. Ferraz, Rolf G. Boot, Marc P. Baggelaar, Mario van der Stelt, Monique Appelman, Gijsbert A. van der Marel, Bogdan I. Florea, Johannes M. F. G. Aerts, and Herman S. Overkleeft. "Development of an acid ceramidase activity-based probe." Chemical Communications 51, no. 28 (2015): 6161–63. http://dx.doi.org/10.1039/c5cc00356c.

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Strelow, Astrid, Katussevani Bernardo, Sabine Adam-Klages, Thomas Linke, Konrad Sandhoff, Martin Krönke, and Dieter Adam. "Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor–Induced Cell Death." Journal of Experimental Medicine 192, no. 5 (August 28, 2000): 601–12. http://dx.doi.org/10.1084/jem.192.5.601.

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Tumor necrosis factor (TNF) signals cell death and simultaneously induces generation of ceramide. To evaluate the contribution of ceramide to TNF-dependent cell death, we generated clones of the TNF-sensitive cell line L929 that constitutively overexpress human acid ceramidase (AC). Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation. In response to TNF, parental L929 cells display a significant increase in intracellular ceramide correlated with an “atypical apoptosis” characterized by membrane blebbing, DNA fragmentation and degradation of poly(ADP-ribose) polymerase despite a lack of caspase activity. These features are strongly reduced or absent in AC-overexpressing cells. Pharmacological suppression of AC with N-oleoylethanolamine restored the accumulation of intracellular ceramide as well as the sensitivity of the transfectants to TNF, implying that an enhanced metabolization of intracellular ceramide by AC shifts the balance between intracellular ceramide and SPP levels towards cell survival. Correspondingly, inhibition of ceramide production by acid sphingomyelinase also increased survival of TNF-treated L929 cells.

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Kato, H., K. Nemoto, M. Shimizu, A. Abe, S. Asai, N. Ishihama, S. Matsuoka, et al. "Recognition of pathogen-derived sphingolipids in Arabidopsis." Science 376, no. 6595 (May 20, 2022): 857–60. http://dx.doi.org/10.1126/science.abn0650.

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In plants, many invading microbial pathogens are recognized by cell-surface pattern recognition receptors, which induce defense responses. Here, we show that the ceramide Phytophthora infestans –ceramide D (Pi-Cer D) from the plant pathogenic oomycete P. infestans triggers defense responses in Arabidopsis . Pi-Cer D is cleaved by an Arabidopsis apoplastic ceramidase, NEUTRAL CERAMIDASE 2 (NCER2), and the resulting 9-methyl–branched sphingoid base is recognized by a plasma membrane lectin receptor–like kinase, RESISTANT TO DFPM-INHIBITION OF ABSCISIC ACID SIGNALING 2 (RDA2). 9-Methyl–branched sphingoid base is specific to microbes and induces plant immune responses by physically interacting with RDA2. Loss of RDA2 or NCER2 function compromised Arabidopsis resistance against an oomycete pathogen. Thus, we elucidated the recognition mechanisms of pathogen-derived lipid molecules in plants.

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He, Xingxuan, and Edward H. Schuchman. "Ceramide and Ischemia/Reperfusion Injury." Journal of Lipids 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/3646725.

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Ceramide, a bioactive membrane sphingolipid, functions as an important second messenger in apoptosis and cell signaling. In response to stresses, it may be generated by de novo synthesis, sphingomyelin hydrolysis, and/or recycling of complex sphingolipids. It is cleared from cells through the activity of ceramidases, phosphorylation to ceramide-1-phosphate, or resynthesis into more complex sphingolipids. Ischemia/reperfusion (IR) injury occurs when oxygen/nutrition is rapidly reintroduced into ischemic tissue, resulting in cell death and tissue damage, and is a major concern in diverse clinical settings, including organ resection and transplantation. Numerous reports show that ceramide levels are markedly elevated during IR. Mitochondria are major sites of reactive oxygen species (ROS) production and play a key role in IR-induced and ceramide-mediated cell death and tissue damage. During the development of IR injury, the initial response of ROS and TNF-alpha production activates two major ceramide generating pathways (sphingomyelin hydrolysis and de novo ceramide synthesis). The increased ceramide has broad effects depending on the IR phases, including both pro- and antiapoptotic effects. Therefore, strategies that reduce the levels of ceramide, for example, by modulation of ceramidase and/or sphingomyelinases activities, may represent novel and promising therapeutic approaches to prevent or treat IR injury in diverse clinical settings.

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Correnti, Jason, Chelsea Lin, Jascha Brettschneider, Amy Kuriakose, Sookyoung Jeon, Eleonora Scorletti, Amanke Oranu, et al. "Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice." Journal of Lipid Research 61, no. 7 (May 12, 2020): 983–94. http://dx.doi.org/10.1194/jlr.ra119000446.

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Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

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Laurier-Laurin, Marie-Elaine, Audrée De Montigny, Suzanne Attiori Essis, Michel Cyr, and Guy Massicotte. "Blockade of Lysosomal Acid Ceramidase Induces GluN2B-Dependent Tau Phosphorylation in Rat Hippocampal Slices." Neural Plasticity 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/196812.

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The lysosomal acid ceramidase, an enzyme known to limit intracellular ceramide accumulation, has been reported to be defective in neurodegenerative disorders. We show here that rat hippocampal slices, preincubated with the acid ceramidase inhibitor (ACI) d-NMAPPD, exhibit increased N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in CA1 synapses. The ACI by itself did not interfere with either paired pulse facilitation or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated fEPSPs, indicating that its influence on synaptic transmission is postsynaptic in origin and specific to the NMDA subtype of glutamate receptors. From a biochemical perspective, we observed that Tau phosphorylation at the Ser262 epitope was highly increased in hippocampal slices preincubated with the ACI, an effect totally prevented by the global NMDA receptor antagonist D/L(−)-2-amino-5-phosphonovaleric acid (AP-5), the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), and the GluN2B (but not the GluN2A) receptor antagonist RO25-6981. On the other hand, preincubation of hippocampal slices with the compound KN-62, an inhibitor known to interfere with calcium/calmodulin-dependent protein kinase II (CaMKII), totally abolished the effect of ACI on Tau phosphorylation at Ser262 epitopes. Collectively, these results provide experimental evidence that ceramides play an important role in regulating Tau phosphorylation in the hippocampus via a mechanism dependent on GluN2B receptor subunits and CaMKII activation.

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KITA, Katsuhiro, Noriyuki SUEYOSHI, Nozomu OKINO, Masanori INAGAKI, Hideharu ISHIDA, Makoto KISO, Shuhei IMAYAMA, Takashi NAKAMURA, and Makoto ITO. "Activation of bacterial ceramidase by anionic glycerophospholipids: possible involvement in ceramide hydrolysis on atopic skin by Pseudomonas ceramidase." Biochemical Journal 362, no. 3 (March 8, 2002): 619–26. http://dx.doi.org/10.1042/bj3620619.

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We have reported previously that the ceramidase from Pseudomonas aeruginosa AN17 isolated from a patient with atopic dermatitis requires detergents for hydrolysis of ceramide (Cer) [Okino, Tani, Imayama and Ito (1998) J. Biol. Chem. 273, 14368–14373]. In the present study, we report that some glycerophospholipids strongly activated the hydrolysis of Cer by Pseudomonas ceramidase in the absence of detergents. Among the glycerophospholipids tested, cardiolipin was most effective in stimulating hydrolysis of Cer followed by phosphatidic acid, phosphatidylethanolamine and phosphatidylglycerol, whereas phosphatidylcholine, lysophosphatidic acid and diacylglycerol were less effective. Interestingly, Staphylococcus aureus-derived lipids, which contain cardiolipin and phosphatidylglycerol as major lipid components, also strongly enhanced the hydrolysis of normal Cer, as well as the human skin-specific ω-hydroxyacyl Cer, by the enzyme in the absence of detergents. It was confirmed that several strains of P. aeruginosa, including AN17, secrete a significant amount of staphylolytic proteases to lyse S. aureus cells, resulting in the release of cardiolipin and phosphatidylglycerol. Since both P. aeruginosa and S. aureus are suspected of being present in microflora of atopic skin, we speculate that S. aureus-derived glycerophospholipids stimulate the hydrolysis of Cer in atopic skin by bacterial ceramidase.

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Choi, Moonsuk S., Mary A. Anderson, Zhongjian Zhang, Drazen B. Zimonjic, Nicolae Popescu, and Anil B. Mukherjee. "Neutral ceramidase gene: role in regulating ceramide-induced apoptosis." Gene 315 (October 2003): 113–22. http://dx.doi.org/10.1016/s0378-1119(03)00721-2.

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Bhabak, Krishna P., Denny Proksch, Susanne Redmer, and Christoph Arenz. "Novel fluorescent ceramide derivatives for probing ceramidase substrate specificity." Bioorganic & Medicinal Chemistry 20, no. 20 (October 2012): 6154–61. http://dx.doi.org/10.1016/j.bmc.2012.08.035.

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KITA, Katsuhiro, Noriyuki SUEYOSHI, Nozomu OKINO, Masanori INAGAKI, Hideharu ISHIDA, Makoto KISO, Shuhei IMAYAMA, Takashi NAKAMURA, and Makoto ITO. "Activation of bacterial ceramidase by anionic glycerophospholipids: possible involvement in ceramide hydrolysis on atopic skin by Pseudomonas ceramidase." Biochemical Journal 362, no. 3 (March 15, 2002): 619. http://dx.doi.org/10.1042/0264-6021:3620619.

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Hawkins, Cyntanna, Amber Jones, Julia Ziebro, Emily Gordon, Catherine Libby, Sarah Williford, Jeremy Allegood, et al. "DDRE-06. TARGETING THE SPHINGOLIPID BALANCE VIA ACID CERAMIDASE INHIBITION TO DECREASE GROWTH OF TMZ-RESISTANT GLIOBLASTOMA AND BLOCK MIGRATION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi75. http://dx.doi.org/10.1093/neuonc/noab196.290.

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Abstract Dysregulated sphingolipid metabolism is associated with many cancers; allowing cells to evade apoptosis through increases in sphingosine-1-phosphate (S1P) and decreases in ceramides. Ceramides can be hydrolyzed by ceramidases to sphingosine, which can then be phosphorylated by sphingosine kinases to S1P. S1P allows cells to evade apoptosis and increase migration, while shifts toward ceramides favor cell death. Glioblastoma (GBM) exhibits shifts in the sphingolipid balance towards S1P, contributing to chemoresistance and migration. Understanding of sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target the dysregulation. Acid ceramidase (ASAH1), a key enzyme in the production of S1P, is highly expressed in GBM and is associated with worse survival of GBM patients, as per The Cancer Genome Atlas data. To address the altered sphingolipid metabolism and therapeutic resistance in GBM, we explored the efficacy of pharmacologic and genetic inhibition of ASAH1 in both parental and temozolomide (TMZ)-resistant patient-derived xenografts. Cells were infected with ASAH1 shRNA or treated with ASAH1 inhibitors and assessed for cell growth and migration. Our work suggests that pharmacologic inhibition of ASAH1 induces cell death and that this effect is maintained in TMZ-resistant cells. Furthermore, we find a novel role for carmofur, an ASAH1 inhibitor, in the inhibition of GBM migration. Together, these data suggest the potential utility of normalizing the sphingolipid balance in the context of GBM TMZ resistance.

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Frohbergh, Michael, Xingxuan He, and Edward H. Schuchman. "The molecular medicine of acid ceramidase." Biological Chemistry 396, no. 6-7 (June 1, 2015): 759–65. http://dx.doi.org/10.1515/hsz-2014-0290.

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Abstract Acid ceramidase (N-acylsphingosine deacylase, EC 3.5.1.23; AC) is the lipid hydrolase responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. The enzymatic activity was first identified over four decades ago and is deficient in two rare inherited disorders, Farber lipogranulomatosis (Farber disease) and spinal muscular atrophy with myoclonic epilepsy (SMA-PME). Importantly, AC not only hydrolyzes ceramide into sphingosine within acidic compartments, but also can synthesize ceramide from sphingosine at neutral pH, suggesting that the enzyme may have diverse functions depending on its subcellular location and the local pH. Within cells, AC exists in a complex with other lipid hydrolases and requires a polypeptide cofactor (saposin D) for full hydrolytic activity. Recent studies also have shown that AC is overexpressed in several human cancers, and that inhibition of this enzyme may be a useful cancer drug target. Aberrant AC activity has also been described in several other common diseases. The cDNA and gene (ASAH1) encoding AC have been isolated, several mouse models of AC deficiency have been constructed, and the recombinant enzyme is currently being manufactured for the treatment of Farber disease and SMA-PME. Current information concerning the biology of this enzyme and its role in human disease is reviewed within.

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Ferlinz, Klaus, Guido Kopal, Katussevani Bernardo, Thomas Linke, Julia Bär, Bernadette Breiden, Ulrich Neumann, Florian Lang, Edward H. Schuchman, and Konrad Sandhoff. "Human Acid Ceramidase." Journal of Biological Chemistry 276, no. 38 (July 12, 2001): 35352–60. http://dx.doi.org/10.1074/jbc.m103066200.

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Lu, Ping, Shai White-Gilbertson, Gyda Beeson, Craig Beeson, Besim Ogretmen, James Norris, and Christina Voelkel-Johnson. "Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells." Cancers 13, no. 9 (May 5, 2021): 2212. http://dx.doi.org/10.3390/cancers13092212.

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Polyploid giant cancer cells (PGCC) constitute a transiently senescent subpopulation of cancer cells that arises in response to stress. PGCC are capable of generating progeny via a primitive, cleavage-like cell division that is dependent on the sphingolipid enzyme acid ceramidase (ASAH1). The goal of this study was to understand differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells to gain an understanding of the ASAH1-dependence in the PGCC population. Steady-state and flux analysis of sphingolipids did not support our initial hypothesis that the ASAH1 product sphingosine is rapidly converted into the pro-survival lipid sphingosine-1-phosphate. Instead, our results suggest that ASAH1 activity is important for preventing the accumulation of long chain ceramides such as C16-ceramide. We therefore determined how modulation of C16-ceramide, either through CerS6 or p53, a known PGCC suppressor and enhancer of CerS6-derived C16-ceramide, affected PGCC progeny formation. Co-expression of the CerS6 and p53 abrogated the ability of PGCC to form offspring, suggesting that the two genes form a positive feedback loop. CerS6 enhanced the effect of p53 by significantly increasing protein half-life. Our results support the idea that sphingolipid metabolism is of functional importance in PGCC and that targeting this signaling pathway has potential for clinical intervention.

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Klemetti, Miira M., Sruthi Alahari, Martin Post, and Isabella Caniggia. "Distinct Changes in Placental Ceramide Metabolism Characterize Type 1 and 2 Diabetic Pregnancies with Fetal Macrosomia or Preeclampsia." Biomedicines 11, no. 3 (March 17, 2023): 932. http://dx.doi.org/10.3390/biomedicines11030932.

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Disturbances of lipid metabolism are typical in diabetes. Our objective was to characterize and compare placental sphingolipid metabolism in type 1 (T1D) and 2 (T2D) diabetic pregnancies and in non-diabetic controls. Placental samples from T1D, T2D, and control pregnancies were processed for sphingolipid analysis using tandem mass spectrometry. Western blotting, enzyme activity, and immunofluorescence analyses were used to study sphingolipid regulatory enzymes. Placental ceramide levels were lower in T1D and T2D compared to controls, which was associated with an upregulation of the ceramide degrading enzyme acid ceramidase (ASAH1). Increased placental ceramide content was found in T1D complicated by preeclampsia. Similarly, elevated ceramides were observed in T1D and T2D pregnancies with poor glycemic control. The protein levels and activity of sphingosine kinases (SPHK) that produce sphingoid-1-phosphates (S1P) were highest in T2D. Furthermore, SPHK levels were upregulated in T1D and T2D pregnancies with fetal macrosomia. In vitro experiments using trophoblastic JEG3 cells demonstrated increased SPHK expression and activity following glucose and insulin treatments. Specific changes in the placental sphingolipidome characterize T1D and T2D placentae depending on the type of diabetes and feto-maternal complications. Increased exposure to insulin and glucose is a plausible contributor to the upregulation of the SPHK-S1P-axis in diabetic placentae.

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Ohnishi, Yoshinori, Nozomu Okino, Makoto Ito, and Shuhei Imayama. "Ceramidase Activity in Bacterial Skin Flora as a Possible Cause of Ceramide Deficiency in Atopic Dermatitis." Clinical Diagnostic Laboratory Immunology 6, no. 1 (January 1, 1999): 101–4. http://dx.doi.org/10.1128/cdli.6.1.101-104.1999.

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ABSTRACT A marked decrease in the content of ceramide has been reported in the horny layer of the epidermis in atopic dermatitis (AD). This decrease impairs the permeability barrier of the epidermis, resulting in the characteristic dry and easily antigen-permeable skin of AD, since ceramide serves as the major water-holding molecule in the extracellular space of the horny layer. On the other hand, the skin of such patients is frequently colonized by bacteria, most typically byStaphylococcus aureus, possessing genes such as those for sphingomyelinase, which are related to sphingolipid metabolism. We therefore tried to identify a possible correlation between the ceramide content and the bacterial flora obtained from the skin of 25 patients with AD versus that of 24 healthy subjects, using a thin-layer chromatographic assay of the sphingomyelin-associated enzyme activities secreted from the bacteria. The findings of the assay demonstrated that ceramidase, which breaks ceramide down into sphingosine and fatty acid, was secreted significantly more from the bacterial flora obtained from both the lesional and the nonlesional skin of patients with AD than from the skin of healthy subjects; sphingomyelinase, which breaks sphingomyelin down into ceramide and phosphorylcholine, was secreted from the bacterial flora obtained from all types of skin at similar levels for the patients with AD and the healthy controls. The finding that the skin of patients with AD is colonized by ceramidase-secreting bacteria thus suggests that microorganisms are related to the deficiency of ceramide in the horny layer of the epidermis, which increases the hypersensitivity of skin in AD patients by impairing the permeability barrier.

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ZAGER, RICHARD A., KRISTIN M. BURKHART, and ALI JOHNSON. "Sphingomyelinase and Membrane Sphingomyelin Content." Journal of the American Society of Nephrology 11, no. 5 (May 2000): 894–902. http://dx.doi.org/10.1681/asn.v115894.

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Abstract. Ceramides acutely accumulate in proximal tubules during injury. Pathogenic relevance of this change is suggested by observations that adding ceramide to tubular cells alters superimposed hypoxic and toxic attack. Ceramide accumulation during cell injury is thought to arise from sphingomyelinase (SMase)-mediated sphingomyelin (SM) hydrolysis ± decreased catabolism. Thus, ceramide addition to cells cannot precisely simulate pathophysiologic events. Therefore, this study assessed direct effects of SMase activity on tubular cell viability under basal conditions and during superimposed attack. Cultured human proximal tubule (HK-2) cells were exposed to differing SMase doses. Its effects on cell phospholipids, ceramides, proliferation rates, and susceptibility to injury (ATP depletion, Fe-mediated oxidant stress) were assessed. Because SMase reduces cell SM content, the effect of exogenous SM on membrane injury (intact cells, isolated vesicles) was also tested. Finally, because SM decreases membrane fluidity, the impact of a fluidizing agent (A2C) on membrane injury (phospholipase A2, lipid peroxidation) was addressed. SMase reduced HK-2 SM content by approximately 33%, but only modest ceramide increments resulted (suggesting high endogenous ceramidase activity). SMase, by itself, caused no cell death (lactate dehydrogenase release). However, it was mildly antiproliferative, and it dramatically predisposed to both ATP depletion- and Fe-mediated attack. SMase also predisposed isolated vesicles to damage, suggesting that its impact on intact cells reflects a direct membrane effect. Adding SM to intact cells (or vesicles) mitigated ATP depletion and Fe- and phospholipase A2-induced damage. In contrast, A2C rendered membranes more vulnerable to attack. SMase predisposes tubular cells to superimposed ATP depletion and oxidant injury. This may be explained by SM losses, and not simply cytotoxic ceramide gains, given that SM can directly decrease cell/membrane damage. The ability of SM to decrease membrane fluidity may explain, at least in part, its cytoprotective effect.

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Ikarashi, Nobutomo, Wataru Sato, Takahiro Toda, Makoto Ishii, Wataru Ochiai, and Kiyoshi Sugiyama. "Inhibitory Effect of Polyphenol-Rich Fraction from the Bark ofAcacia mearnsiion Itching Associated with Allergic Dermatitis." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/120389.

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We examined the inhibitory effect of polyphenol-rich aqueous extract from the bark ofAcacia mearnsii(PrA) on itching associated with atopic dermatitis (AD). HR-1 mice were fed a normal diet, special diet (AD group), or special diet containing 3% PrA (PrA group) for 6 weeks. In the AD group, itching frequency and transepidermal water loss increased compared to the control group. In the PrA group, an improvement in atopic dermatitis symptoms was observed. Ceramide expression in the skin decreased in the AD group compared to the control group, but no decrease was observed in the PrA group. mRNA expression of ceramidase decreased in the PrA group compared to the AD group. The results of this study have revealed that PrA inhibits itching in atopic dermatitis by preventing the skin from drying. It is considered that the mechanism by which PrA prevents the skin from drying involves the inhibition of increased ceramidase expression associated with atopic dermatitis.

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Hadas, Yoav, Adam S. Vincek, Elias Youssef, Magdalena M. Żak, Elena Chepurko, Nishat Sultana, Mohammad Tofael Kabir Sharkar, et al. "Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction." Circulation 141, no. 11 (March 17, 2020): 916–30. http://dx.doi.org/10.1161/circulationaha.119.041882.

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Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.

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Keitsch, Simone, Joachim Riethmüller, Matthias Soddemann, Carolin Sehl, Barbara Wilker, Michael J. Edwards, Charles C. Caldwell, Martin Fraunholz, Erich Gulbins, and Katrin Anne Becker. "Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin." Biological Chemistry 399, no. 10 (September 25, 2018): 1203–13. http://dx.doi.org/10.1515/hsz-2018-0161.

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Abstract Pulmonary infections of cystic fibrosis (CF) patients with Staphylococcus aureus (S. aureus) occur very early in the disease. The molecular details that cause infection-susceptibility of CF patients to and mediate infection with S. aureus are poorly characterized. Therefore, we aimed to identify the role of α-toxin, a major S. aureus toxin, for pulmonary infection of CF mice. Infection with S. aureus JE2 resulted in severe pneumonia in CF mice, while wildtype mice were almost unaffected. Deficiency of α-toxin in JE2-Δhla reduced the pathogenicity of S. aureus in CF mice. However, CF mice were still more susceptible to the mutant S. aureus strain than wildtype mice. The S. aureus JE2 induced a marked increase of ceramide and a downregulation of sphingosine and acid ceramidase expression in bronchi of CF mice. Deletion of α-toxin reduced these changes after infection of CF mice. Similar changes were observed in wildtype mice, but at much lower levels. Our data indicate that expression of α-toxin is a major factor causing S. aureus infections in CF mice. Wildtype S. aureus induces a marked increase of ceramide and a reduction of sphingosine and acid ceramidase expression in bronchial epithelial cells of wildtype and CF mice, changes that determine infection susceptibility.

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Wang, Chunyan, Juan Pablo Palavicini, and Xianlin Han. "A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions." International Journal of Molecular Sciences 22, no. 21 (October 21, 2021): 11358. http://dx.doi.org/10.3390/ijms222111358.

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Many lipids, including sphingolipids, are essential components of the nervous system. Sphingolipids play critical roles in maintaining the membrane structure and integrity and in cell signaling. We used a multi-dimensional mass spectrometry-based shotgun lipidomics platform to selectively analyze the lipid species profiles of ceramide, sphingomyelin, cerebroside, and sulfatide; these four classes of sphingolipids are found in the central nervous system (CNS) (the cerebrum, brain stem, and spinal cord) and peripheral nervous system (PNS) (the sciatic nerve) tissues of young adult wild-type mice. Our results revealed that the lipid species profiles of the four sphingolipid classes in the different nervous tissues were highly distinct. In addition, the mRNA expression of sphingolipid metabolism genes—including the ceramidase synthases that specifically acylate the N-acyl chain of ceramide species and sphingomyelinases that cleave sphingomyelins generating ceramides—were analyzed in the mouse cerebrum and spinal cord tissue in order to better understand the sphingolipid profile differences observed between these nervous tissues. We found that the distinct profiles of the determined sphingolipids were consistent with the high selectivity of ceramide synthases and provided a potential mechanism to explain region-specific CNS ceramide and sphingomyelin levels. In conclusion, we portray for the first time a lipidomics atlas of select sphingolipids in multiple nervous system regions and believe that this type of knowledge could be very useful for better understanding the role of this lipid category in the nervous system.

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ZHANG, XIAOJING, XINYAN KONG, CUI YANG, WENQI LIU, ZHIWEN ZOU, BIN XIA, and TIANRONG XIN. "Ceramidase is involved in the development and reproduction of Panonychus citri." Zoosymposia 22 (November 30, 2022): 254. http://dx.doi.org/10.11646/zoosymposia.22.1.155.

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As the second largest lipid, sphingolipids play an important role in the growth and development of organisms. However, due to the complexity and diversity of their molecular structures, the knowledge about the structure and function of sphingolipids remians unclear for many insects and mites. Ceramidase, as an important sphingolipid substance, maintains cell survival by regulating the dynamic balance between ceramide and sphingosine. In order to study the role of ceramidase in the growth and development of Panonychus citri, the full-length cDNA sequence of ceramidase (CDase) gene was cloned by RT-PCR combined with RACE technology for the first time. The results showed that the full-length of Ceramidase cDNA sequence was 1841 bp , including a 164-bp 5′-UTR, a 1572-bp ORF , and a 105-bp 3-UTR and encodes a deduced protein of 523 amino acids. Amino acid sequence alignment showed that CDase gene had the highest homology with that of Tetranychus urticae and the closest genetic relationship with it. In addition, quantitative analysis using RT-qPCR of the gene expression levels of CDase during different developmental stages demonstrated that the CDase gene was expressed during all developmental stages of P. citri, and the relative expression in larvae was significantly higher than those in other stages. Furthermore, RNAi technology was used to silence CDase gene of P. citri, and the corresponding expression and mortality analysis were observed under different concentration gradients (1500ng/ul, 2000ng/ul, 2500ng/ul) and time gradients (24h, 48h). The dsRNA treatment of CDase gene showed a decrease in gene expression. Compared with the control group, the gene expression of CDase in the dsRNA treatment at 2000 ng/ul decreased by 72%, and the mortality rate of adult females increased by 40%. Furthermore, CDase genes treated with dsRNA also decreased by 78% within 48 hours. In general, the interference effect of dsRNA at 2000 ng/ul and 48h was the best, compared with the control group. Our findings will provide insight into the molecular mechanisms regulating lipid metabolism in P. citri.

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Casasampere, Mireia, Núria Bielsa, Daniel Riba, Laura Bassas, Ruijuan Xu, Cungui Mao, Gemma Fabriàs, José-Luis Abad, Antonio Delgado, and Josefina Casas. "New fluorogenic probes for neutral and alkaline ceramidases." Journal of Lipid Research 60, no. 6 (March 29, 2019): 1174–81. http://dx.doi.org/10.1194/jlr.d092759.

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New fluorogenic ceramidase substrates derived from the N-acyl modification of our previously reported probes (RBM14) are reported. While none of the new probes were superior to the known RBM14C12 as acid ceramidase substrates, the corresponding nervonic acid amide (RBM14C24:1) is an efficient and selective substrate for the recombinant human neutral ceramidase, both in cell lysates and in intact cells. A second generation of substrates, incorporating the natural 2-(N-acylamino)-1,3-diol-4-ene framework (compounds RBM15) is also reported. Among them, the corresponding fatty acyl amides with an unsaturated N-acyl chain can be used as substrates to determine alkaline ceramidase (ACER)1 and ACER2 activities. In particular, compound RBM15C18:1 has emerged as the best fluorogenic probe reported so far to measure ACER1 and ACER2 activities in a 96-well plate format.

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Usta, Julnar, Samer El Bawab, Patrick Roddy, Zdzislaw M. Szulc, Yusuf, A. Hannun, and Alicja Bielawska. "Structural Requirements of Ceramide and Sphingosine Based Inhibitors of Mitochondrial Ceramidase†." Biochemistry 40, no. 32 (August 2001): 9657–68. http://dx.doi.org/10.1021/bi010535k.

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Airola, Michael V., William J. Allen, Michael J. Pulkoski-Gross, Lina M. Obeid, Robert C. Rizzo, and Yusuf A. Hannun. "Structural Basis for Ceramide Recognition and Hydrolysis by Human Neutral Ceramidase." Structure 23, no. 8 (August 2015): 1482–91. http://dx.doi.org/10.1016/j.str.2015.06.013.

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Realini, Natalia, Francesca Palese, Daniela Pizzirani, Silvia Pontis, Abdul Basit, Anders Bach, Anand Ganesan, and Daniele Piomelli. "Acid Ceramidase in Melanoma." Journal of Biological Chemistry 291, no. 5 (November 9, 2015): 2422–34. http://dx.doi.org/10.1074/jbc.m115.666909.

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Alsamman, Sarah, Stephanie A. Christenson, Amy Yu, Nadia M. E. Ayad, Meghan S. Mooring, Joe M. Segal, Jimmy Kuang-Hsien Hu, et al. "Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice." Science Translational Medicine 12, no. 557 (August 19, 2020): eaay8798. http://dx.doi.org/10.1126/scitranslmed.aay8798.

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Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.

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Lai, Michele, Veronica La Rocca, Rachele Amato, Giulia Freer, Mario Costa, Pietro Giorgio Spezia, Paola Quaranta, Giuseppe Lombardo, Daniele Piomelli, and Mauro Pistello. "Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells." International Journal of Molecular Sciences 22, no. 6 (March 23, 2021): 3247. http://dx.doi.org/10.3390/ijms22063247.

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Cutaneous melanoma is often resistant to therapy due to its high plasticity, as well as its ability to metabolise chemotherapeutic drugs. Sphingolipid signalling plays a pivotal role in its progression and metastasis. One of the ways melanoma alters sphingolipid rheostat is via over-expression of lysosomal acid ceramidase (AC), which catalyses the hydrolysis of pro-apoptotic long-chain ceramides into sphingosine and fatty acid. In this report, we examine the role of acid ceramidase in maintaining cellular homeostasis through the regulation of autophagy and mitochondrial activity in melanoma cell lines. We show that under baseline conditions, wild-type melanoma cells had 3-fold higher levels of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3 II), compared to AC-null cells. This difference was further magnified after cell starvation. Moreover, we noticed autophagy impairment in A375 AC-null cells, possibly due to local accumulation of non-metabolized ceramides. Nonetheless, we observed that AC-null cells exhibited a significant increase in mitochondrial membrane potential compared to control cells. Consistent with this observation, we found that, after total starvation, ~30% of AC-null cells undergo apoptosis compared to ~6% of wild-type cells. As expected, AC transfection restored viability in A375 AC-null cells. Together, these findings suggest that AC-null melanoma cells change and adapt their metabolism to survive in the absence of AC, although in a way that does not allow them to cope with the stress of nutrient deprivation.

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Hajj, Carla, Katrin Anne Becker-Flegler, and Adriana Haimovitz-Friedman. "Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways." Biological Chemistry 396, no. 6-7 (June 1, 2015): 669–79. http://dx.doi.org/10.1515/hsz-2014-0302.

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Abstract The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents.

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Jan, Jia-Tsrong, Subroto Chatterjee, and Diane E. Griffin. "Sindbis Virus Entry into Cells Triggers Apoptosis by Activating Sphingomyelinase, Leading to the Release of Ceramide." Journal of Virology 74, no. 14 (July 15, 2000): 6425–32. http://dx.doi.org/10.1128/jvi.74.14.6425-6432.2000.

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ABSTRACT Sindbis virus (SV) causes acute encephalomyelitis by infecting and inducing the death of neurons. Induction of apoptosis occurs during virus entry and involves acid-induced conformational changes in the viral surface glycoproteins and sphingomyelin (SM)-dependent fusion of the virus envelope with the endosomal membrane. We have studied neuroblastoma cells to determine how this entry process triggers cell death. Acidic sphingomyelinase was activated during entry followed by activation of neutral sphingomyelinase, SM degradation, and a sustained increase in ceramide. Ceramide-induced apoptosis and SV-induced apoptosis could be inhibited by treatment with Z-VAD-fmk, a caspase inhibitor, and by overexpression of Bcl-2, an antiapoptotic cellular protein. Acid ceramidase, expressed in a recombinant SV, decreased intracellular ceramide and protected cells from apoptosis. The data suggest that acid-induced SM-dependent virus fusion initiates the apoptotic cascade by inducing SM degradation and ceramide release.

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Inoue, Tsuyoshi, Nozomu Okino, Yoshimitsu Kakuta, Atsushi Hijikata, Hiroyuki Okano, Hatsumi M. Goda, Motohiro Tani, et al. "Mechanistic Insights into the Hydrolysis and Synthesis of Ceramide by Neutral Ceramidase." Journal of Biological Chemistry 284, no. 14 (December 16, 2008): 9566–77. http://dx.doi.org/10.1074/jbc.m808232200.

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Park, Jae-Ho, and Suk Hoo Yoon. "Ceramide, a crucial functional lipid, and its metabolic regulation by acid ceramidase." Food Science and Biotechnology 19, no. 4 (August 2010): 859–64. http://dx.doi.org/10.1007/s10068-010-0122-y.

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Rajah.R, Nirmal, and Rufus Auxillia. "Phylogenetic Analysis of Neutral Ceramidase." International Journal of Computer Applications 108, no. 7 (December 18, 2014): 18–23. http://dx.doi.org/10.5120/18923-0271.

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Journal articles on the topic 'Ceramidase'

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