Regulation of Arthritis Severity by the Acid Sphingomyelinase

Beckmann, Nadine; Becker, Katrin Anne; Walter, Silke; Becker, Jan Ulrich; Krämer, Markus; Hessler, Gabriele; Weber, Stefanie; Göthert, Joachim R.; Faßbender, Klaus; Gulbins, Erich; Carpinteiro, Alexander

doi:10.1159/000481968

Cited by 24 publications

(20 citation statements)

References 62 publications

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“…The interaction between lyso-PLs and ceramides is likely to take place in cell membranes if the local concentrations of ceramides and lyso-PLs are coordinately increased as a result of, for example, the activation of phospholipase A 2 and sphingomyelinase. Such a scenario could be possible during inflammatory processes when both acid sphingomyelinase and secretory phospholipase A 2 have been shown to be active and involved in inflammatory processes (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Natural Ceramides and Lysophospholipids Cosegregate in Fluid Phosphatidylcholine Bilayers

Sazzad

Möuts

Palacios-Ortega

et al. 2019

Biophysical Journal

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The mode of interactions between palmitoyl lysophosphatidylcholine (palmitoyl lyso-PC) or other lysophospholipids (lyso-PLs) and palmitoyl ceramide (PCer) or other ceramide analogs in dioleoylphosphatidylcholine (DOPC) bilayers has been examined. PCer is known to segregate laterally into a ceramide-rich phase at concentrations that depend on the nature of the ceramides and the co-phospholipids. In DOPC bilayers, PCer forms a ceramide-rich phase at concentrations above 10 mol%. In the presence of 20 mol% palmitoyl lyso-PC in the DOPC bilayer, the lateral segregation of PCer was markedly facilitated (segregation at lower PCer concentrations). The thermostability of the PCer-rich phase in the presence of palmitoyl lyso-PC was also increased compared to that in the absence of palmitoyl lyso-PC. Other saturated lyso-PLs (e.g., palmitoyl lyso-phosphatidylethanolamine and lyso-sphingomyelin) also facilitated the lateral segregation of PCer in a similar manner as palmitoyl lyso-PC. When examined in the DOPC bilayer, it appeared that the association between palmitoyl lyso-PC and PCer was equimolar in nature. It is proposed that the interaction of PCer with lyso-PLs was driven by the need of ceramide to obtain a large-headgroup co-lipid, and saturated lyso-PLs were preferred co-lipids over DOPC because of the nature of their acyl chain. Structural analogs of PCer (1-or 3-deoxy-PCer) were also associated with palmitoyl lyso-PC, similarly to PCer, suggesting that the ceramide/lyso-PL interaction was not sensitive to structural alterations in the ceramide molecule. Binary complexes containing palmitoyl lyso-PC and ceramide were prepared, and these had a bilayer structure as ascertained by transmission electron microscopy. It is concluded that ceramides and lyso-PLs associated with each other both in binary bilayers and in ternary systems based on the DOPC bilayers. This association may have biological relevance under conditions in which both sphingomyelinases and phospholipase A 2 enzymes are activated, such as during inflammatory processes.

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Section: Discussionmentioning

confidence: 99%

Natural Ceramides and Lysophospholipids Cosegregate in Fluid Phosphatidylcholine Bilayers

Sazzad

Möuts

Palacios-Ortega

et al. 2019

Biophysical Journal

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“…Mice with ASMase deficiency are animal models for human type A or B Niemann–Pick disease, which is a lysosomal lipid storage disease characterized with hepatosplenomegaly and neurological symptoms (Schuchman & Wasserstein, ). In addition to the studies on the pathogenesis of human type A or B Niemann–Pick disease, mice with ASMase deficiency have been also used as animal model by a large number of studies to define the role of ASMase in human inflammatory diseases (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini, Xia, Koka, Gehr, & Li, ; Chung et al, ; Dannhausen et al, ; Dhami, He, & Schuchman, ; Hoehn et al, ; Ikegami, Dhami, & Schuchman, ; Nakatsuji, Tang, Zhang, Gallo, & Huang, ; Novgorodov et al, ; Opreanu et al, ; Osawa et al, ). Interestingly, while most of these studies demonstrated that ASMase deficiency attenuated inflammation (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini et al, ; Chung et al, ; Dhami et al, ; Hoehn et al, ; Nakatsuji et al, ; Novgorodov et al, ; Opreanu et al, ), a few studies showed that ASMase deficiency enhanced inflammation (Dannhausen et al, ; Ikegami et al, ; Osawa et al, ).…”

Section: Introductionmentioning

confidence: 99%

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

Zhang

et al. 2020

Oral Diseases

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Background Mutation of the gene for acid sphingomyelinase (ASMase) causes Niemann–Pick disease. However, the effect of ASMase deficiency on periodontal health is unknown. Periodontal disease is a disease resulting from infection and inflammation of periodontal tissue and alveolar bone that support the teeth. The goal of this study was to determine the role of ASMase deficiency in periodontal inflammation and alveolar bone loss. Methods We induced periodontitis in wild‐type and ASMase‐deficient (ASMase−/−) mice with periodontal lipopolysaccharide (LPS) injection and compared the alveolar bone loss and periodontal inflammation between these mice. Results Results showed that ASMase deficiency did not significantly change metabolic parameters, but exacerbated LPS‐induced alveolar bone loss, osteoclastogenesis, and periodontal tissue inflammation. To understand the mechanisms by which ASMase deficiency aggravates LPS‐induced periodontitis, we analyzed sphingolipids in periodontal tissues. Results showed that ASMase deficiency led to increases in not only sphingomyelin, but also ceramide (CER), a bioactive sphingolipid known to promote inflammation. Results further showed that ASMase deficiency increased CER de novo synthesis. Conclusion ASMase deficiency exacerbated LPS‐induced alveolar bone loss and periodontal inflammation. ASMase deficiency leads to an unexpected CER increase by stimulating de novo synthesis CER, which is likely to be involved in the ASMase deficiency‐exacerbated periodontitis.

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“…In addition, mice in groups 2 and 4 received intraperitoneal injection of amitriptyline (0.5 mg•mouse Ϫ1 •day Ϫ1 ) while mice in groups 3 and 6 received intraperitoneal injection of GW4869 (0.1 mg•mouse Ϫ1 •day Ϫ1 ). The above dose of amitriptyline and the route of amitriptyline administration were reported to be effective in inhibiting ASMase in mice (4,37). The above dose of GW4869 and the route of GW4869 administration were also reported to be effective in inhibiting NSMase in mice (23,35).…”

Section: Methodsmentioning

confidence: 94%

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism

Syn

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR−/−) mice. LDLR−/− mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR−/− mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.

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Regulation of Arthritis Severity by the Acid Sphingomyelinase

Cited by 24 publications

References 62 publications

Natural Ceramides and Lysophospholipids Cosegregate in Fluid Phosphatidylcholine Bilayers

Natural Ceramides and Lysophospholipids Cosegregate in Fluid Phosphatidylcholine Bilayers

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism

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