scholarly journals Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1573 ◽  
Author(s):  
Farzana Parveen ◽  
Daniel Bender ◽  
Shi-Hui Law ◽  
Vineet Kumar Mishra ◽  
Chih-Chieh Chen ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Tissue Expression ◽  
Human Diseases ◽  
Sphingolipid Metabolism ◽  
Acid Ceramidase ◽  
Sphingosine 1 Phosphate ◽  
Divergence Structure ◽  
Altered Lipid

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.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

scholarly journals The Sphingolipid Asset Is Altered in the Nigrostriatal System of Mice Models of Parkinson’s Disease

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 93
Author(s):  
Victor Blokhin ◽  
Maria Shupik ◽  
Ulyana Gutner ◽  
Ekaterina Pavlova ◽  
Albert T. Lebedev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sphingolipid Metabolism ◽  
Nigrostriatal System ◽  
Dopaminergic Cell ◽  
Metabolism Enzymes ◽  
Clinical Stages ◽  
Sphingosine 1 Phosphate

Parkinson’s disease (PD) is a neurodegenerative disease incurable due to late diagnosis and treatment. Therefore, one of the priorities of neurology is to study the mechanisms of PD pathogenesis at the preclinical and early clinical stages. Given the important role of sphingolipids in the pathogenesis of neurodegenerative diseases, we aimed to analyze the gene expression of key sphingolipid metabolism enzymes (ASAH1, ASAH2, CERS1, CERS3, CERS5, GBA1, SMPD1, SMPD2, UGCG) and the content of 32 sphingolipids (subspecies of ceramides, sphingomyelins, monohexosylceramides and sphinganine, sphingosine, and sphingosine-1-phosphate) in the nigrostriatal system in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of the preclinical and clinical stages of PD. It has been shown that in PD models, the expression of five of the nine studied genes (CERS1, CERS5, ASAH1, ASAH2, and GBA1) increases but only in the substantia nigra (SN) containing dopaminergic cell bodies. Changes in the expression of enzyme genes were accompanied by an increase in the content of 7 of the 32 studied sphingolipids. Such findings suggest these genes as attractive candidates for diagnostic purposes for preclinical and clinical stages of PD.

scholarly journals Macrophage migration inhibitory factor is a novel structure component of centrioles and a novel transcriptional factor

2020 ◽  
Author(s):  
Lu Zhang ◽  
Hongbing Zhang ◽  
Xiaoyan Li ◽  
Ewud Agborbesong ◽  
Xiaogang Li
Keyword(s):  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Nuclear Translocation ◽  
Transcriptional Factor ◽  
Inhibitory Factor ◽  
Human Diseases ◽  
Macrophage Migration ◽  
Novel Structure

Abstract Ciliopathies are a group of human diseases that affect the cellular cilia or the cilia anchoring structures, the bosal bodies, or ciliary function. Macrophage migration inhibitory factor (MIF) as an important inflammatory cytokine plays a prominent role in the pathogenesis of various human diseases. However, the role of MIF in ciliopathies remains elusive. In this study, we show that MIF is a structure protein of basal bodies, which forms a ring-like structure at proximal end of centrioles to regulate cilia assembly and elongation. Importantly, we identify MIF as a novel transcriptional factor, which regulates the expression of ciliary genes and genes associated with different signaling pathways. The phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) mediated MIF phosphorylation at S91 is necessary for the nuclear translocation of MIF, a process that is regulated by 14-3-3ζ. This study suggests that MIF is a key player in cilia biogenesis and transcriptional regulation in homeostasis.

scholarly journals Apolipoprotein M—A Marker or an Active Player in Type II Diabetes?

2021 ◽  
Vol 12 ◽  
Author(s):  
Christina Christoffersen
Keyword(s):  
Cholesterol Metabolism ◽  
High Density Lipoproteins ◽  
Apolipoprotein M ◽  
Active Player ◽  
Sphingosine 1 Phosphate ◽  
Diabetes Development ◽  
Diabetes And Obesity ◽  
Harmful Effects

Apolipoprotein M (apoM) is a member of the lipocalin superfamily and an important carrier of the small bioactive lipid sphingosine-1-phosphate (S1P). The apoM/S1P complex is attached to all lipoproteins, but exhibits a significant preference for high-density lipoproteins. Although apoM, S1P, and the apoM/S1P complex have been discovered more than a decade earlier, the overall function of the apoM/S1P complex remains controversial. Evidence suggests that the complex plays a role in inflammation and cholesterol metabolism and is important for maintaining a healthy endothelial barrier, regulating the turnover of triglycerides from lipoproteins, and reducing cholesterol accumulation in vessel walls. Recent studies have also addressed the role of apoM and S1P in the development of diabetes and obesity. However, limited evidence is available, and the data published so far deviates. This review discusses the specific elements indicative of the protective or harmful effects of apoM, S1P, and the apoM/S1P complex on type 2 diabetes development. Since drugs targeting the S1P system and its receptors are available and could be potentially used for treating diabetes, this research topic is a pertinent one.

scholarly journals Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1682
Author(s):  
Jeanne Guitton ◽  
Cécile L. Bandet ◽  
Mohamed L. Mariko ◽  
Sophie Tan-Chen ◽  
Olivier Bourron ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Current Knowledge ◽  
Sphingolipid Metabolism ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Sphingosine 1 Phosphate

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

scholarly journals Role of Sphingosine Kinase in Type 2 Diabetes Mellitus

2021 ◽  
Vol 11 ◽  
Author(s):  
Yanfei Qi ◽  
Wei Wang ◽  
Ziyu Song ◽  
Gulibositan Aji ◽  
Xin Tracy Liu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
Peripheral Insulin Resistance ◽  
Sphingosine 1 Phosphate ◽  
Druggable Targets

Sphingolipids are a class of essential lipids, functioning as both cell membrane constituents and signaling messengers. In the sphingolipid metabolic network, ceramides serve as the central hub that is hydrolyzed to sphingosine, followed by phosphorylation to sphingosine 1-phosphate (S1P) by sphingosine kinase (SphK). SphK is regarded as a “switch” of the sphingolipid rheostat, as it catalyzes the conversion of ceramide/sphingosine to S1P, which often exhibit opposing biological roles in the cell. Besides, SphK is an important signaling enzyme that has been implicated in the regulation of a wide variety of biological functions. In recent years, an increasing body of evidence has suggested a critical role of SphK in type 2 diabetes mellitus (T2D), although a certain level of controversy remains. Herein, we review recent findings related to SphK in the field of T2D research with a focus on peripheral insulin resistance and pancreatic β-cell failure. It is expected that a comprehensive understanding of the role of SphK and the associated sphingolipids in T2D will help to identify druggable targets for future anti-diabetes therapy.

scholarly journals Role of alarmin cytokines and microRNAs in the host-schistosome interaction

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1571
Author(s):  
Xing He ◽  
Weiqing Pan
Keyword(s):  
Infectious Disease ◽  
Human Diseases ◽  
Effective Vaccine ◽  
Disease Mechanism ◽  
Type 2 Immunity ◽  
Mirna Deregulation

Schistosomiasis is a serious but neglected tropical infectious disease, afflicting more than 240 million people in 78 countries. Lack of an effective vaccine and obscuring disease mechanism could be the main hurdles to effectively control and eradicate this disease. A better understanding of the host–schistosome interaction is the key to clearing these hurdles. Recently, accumulating evidence shows that alarmin cytokines and microRNAs (miRNAs) are crucial regulators in the host–schistosome interaction. Alarmin cytokines are proven to be potent mechanisms driving type 2 immunity, which is the central disease mechanism of schistosomiasis. MiRNA deregulation is a hallmark of a variety of human diseases, including schistosomiasis. In this review, we summarize the research advances on the role of alarmin cytokines and miRNAs in the host–schistosome interaction.

scholarly journals Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qi Chen ◽  
Wei Wang ◽  
Ming-Feng Xia ◽  
You-li Lu ◽  
Hua Bian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Prospective Cohort ◽  
Sphingosine Kinase ◽  
Sphingolipid Metabolism ◽  
Control Group ◽  
Increased Risk ◽  
Sphingosine 1 Phosphate ◽  
Clinical Indices

Abstract Background Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort. Methods Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study. Results Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859). Conclusion Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.

scholarly journals The Role of Sphingolipid Metabolism in Bone Remodeling

2021 ◽  
Vol 9 ◽  
Author(s):  
Tang Qi ◽  
Liao Li ◽  
Tian Weidong
Keyword(s):  
Energy Metabolism ◽  
Molecular Biology ◽  
Bone Diseases ◽  
Sphingolipid Metabolism ◽  
Evidence Based ◽  
Bioactive Lipids ◽  
Cellular Functions ◽  
Sphingosine 1 Phosphate ◽  
Genetically Manipulated

Emerging studies of bioactive lipids have made many exciting discoveries in recent years. Sphingolipids and their metabolites perform a wide variety of cellular functions beyond energy metabolism. Emerging evidence based on genetically manipulated mouse models and molecular biology allows us to obtain new insights into the role sphingolipid played on skeletal remodeling. This review summarizes studies or understandings of the crosstalk between sphingomyelin, ceramide, and sphingosine-1-phosphate (S1P) of sphingolipids family and the cells, especially osteoblasts and osteoclasts of the bone through which bone is remodeled during life constantly. This review also shows agonists and antagonists of S1P as possible therapeutic options and opportunities on bone diseases.

scholarly journals The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes

2021 ◽  
Author(s):  
Laura Bosque‐Plata ◽  
Eduardo Pavel Hernández‐Cortés ◽  
Claudia Gragnoli
Keyword(s):  
Type 2 Diabetes ◽  
Human Diseases ◽  
Pathogenetic Role
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