Sex-Dependent Decrease of Sphingomyelinase Activity During Alcohol Withdrawal Treatment

Mühle, Christiane; Amova, Violina; Biermann, Teresa; Bayerlein, Kristina; Richter‐Schmidinger, Tanja; Kraus, Thomas; Reichel, Martin; Gulbins, Erich; Kornhuber, Johannes

doi:10.1159/000362985

Cited by 23 publications

(19 citation statements)

References 42 publications

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“…High S-ASM activity has been related to reduced skeletal muscle strength (Doehner et al, 2007). In several studies, a negative correlation between S-ASM activity and body mass index (BMI) has been observed (Doehner et al, 2007;Reichel et al, 2011;Mühle et al, 2014), while this has not been detected in other studies (Grammatikos et al, 2014). In patients with chronic heart failure, S-ASM activity increases with age (Doehner et al, 2007), in agreement with studies conducted in mice (Kobayashi et al, 2013).…”

Section: Cross-sectional Clinical Studiessupporting

confidence: 68%

“…In patients with acute myocardial infarction who underwent conventional treatment, high S-ASM activity was observed up to at least day 7 after onset (Pan et al, 2014). If the pathological condition is removed, such as during alcohol withdrawal treatment Mühle et al, 2014), S-ASM activity slowly decreases to control levels. S-ASM activity decreased in survivors, while S-ASM activity further increased in non-survivors (Claus et al, 2005).…”

Section: Longitudinal Clinical Studiesmentioning

confidence: 99%

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Genetic variation within transcriptional regulatory elements and its implications for human disease

Rada-Iglesias¹

2014

Biological Chemistry

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Common human pathologies have a complicated etiology involving both genetic and environmental risk factors. Moreover, the genetic basis of these disorders is also complex, with multiple and weak genetic variants contributing to disease susceptibility. In addition, most of these risk genetic variants occur outside genes, within the vast non-coding human genomic space. In this review I first illustrate how large-scale genomic studies aimed at mapping cis-regulatory elements in the human genome are facilitating the identification of disease-causative non-coding genetic variation. I then discuss some of the challenges that remain to be solved before the pathological consequences of non-coding genetic variation can be fully appreciated. Ultimately, revealing the genetics of human complex disease can be a critical step towards more personalized and effective diagnosis and treatments.

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Section: Cross-sectional Clinical Studiessupporting

confidence: 68%

Section: Longitudinal Clinical Studiesmentioning

confidence: 99%

Genetic variation within transcriptional regulatory elements and its implications for human disease

Rada-Iglesias¹

2014

Biological Chemistry

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“…It might be possible to change endothelial sphingolipids by nutrition [49], although it is not known whether these effects would be strong enough to reduce ceramide formation. It might be also possible that polymorphisms and the sex influence the activity of the acid sphingomyelinase in and the release of ceramide from endothelial cells [50,51], in particular since major depression seems to be more common in women. However, the role of these factors for the release of ceramide from endothelial cells must be carefully explored and is beyond the focus of the present manuscript.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide

Gulbins¹,

Grassmé

Hoehn³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants. Methods: Here, we investigated (i) whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosterone-mediated stress, (ii) whether ceramide is released into the extracellular space of the hippocampus and (iii) whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hippocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with Cy3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts. Results: Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co-application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the hippocampus reduced proliferation of neurons in vitro. Conclusion: The data suggest a novel model for the pathogenesis of major depressive disorder, i.e. the release of ceramide-enriched microvesicles from endothelial cells that negatively affect neuronal proliferation in the hippocampus, but may also induce cardiovascular disease and other systemic symptoms of patients with major depressive disorder.

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“…The slow turnover of S-ASM indicates that small persistent changes in the release of S-ASM result in profound and long-lasting changes in peripheral S-ASM activity. If the pathological condition is removed, such as during alcohol withdrawal treatment Mühle et al, 2014), S-ASM activity slowly decreases to control levels. This underscores the notion of increased ASM activity as a state marker of disease.…”

Section: Longitudinal Clinical Studiesmentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

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122

138

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Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

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Sex-Dependent Decrease of Sphingomyelinase Activity During Alcohol Withdrawal Treatment

Cited by 23 publications

References 42 publications

Genetic variation within transcriptional regulatory elements and its implications for human disease

Genetic variation within transcriptional regulatory elements and its implications for human disease

Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide

Secretory sphingomyelinase in health and disease

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