scholarly journals Antioxidants Supplementation Reduces Ceramide Synthesis Improving the Cardiac Insulin Transduction Pathway in a Rodent Model of Obesity

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3413
Author(s):  
Katarzyna Hodun ◽  
Klaudia Sztolsztener ◽  
Adrian Chabowski
Keyword(s):  
Lipid Metabolism ◽  
Insulin Signaling ◽  
High Performance ◽  
Sphingolipid Metabolism ◽  
Intragastric Administration ◽  
Transduction Pathway ◽  
Ceramide Synthesis ◽  
Sphingosine 1 Phosphate ◽  
Male Wistar Rats ◽  
Ceramide Accumulation

Obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism, and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.

scholarly journals The Sphingosine-1-Phosphate Analog FTY720 Reduces Muscle Ceramide Content and Improves Glucose Tolerance in High Fat-Fed Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Clinton R. Bruce ◽  
Steve Risis ◽  
Joanne R. Babb ◽  
Christine Yang ◽  
Robert S. Lee-Young ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Whole Body ◽  
Sphingolipid Metabolism ◽  
High Fat ◽  
Sphingosine 1 Phosphate ◽  
Ceramide Content ◽  
Ceramide Accumulation

FTY720 is a sphingosine-1-phosphate analog that has been shown to inhibit ceramide synthesis in vitro. Because ceramide accumulation in muscle is associated with insulin resistance, we aimed to examine whether FTY720 would prevent muscle ceramide accumulation in high fat-fed mice and subsequently improve glucose homeostasis. Male C57Bl/6 mice were fed either a chow or high fat-diet (HFD) for 6 wk, after which they were treated with vehicle or FTY720 (5 mg/kg) daily for a further 6 wk. The ceramide content of muscle was examined and insulin action was assessed. Whereas the HFD increased muscle ceramide, this was prevented by FTY720 treatment. This was not associated with alterations in the expression of genes involved in sphingolipid metabolism. Interestingly, the effects of FTY720 on lipid metabolism were not limited to ceramide because FTY720 also prevented the HFD-induced increase in diacylglycerol and triacylglycerol in muscle. Furthermore, the increase in CD36 mRNA expression induced by fat feeding was prevented in muscle of FTY720-treated mice. This was associated with an attenuation of the HFD-induced increase in palmitate uptake and esterification. In addition, FTY720 improved glucose homeostasis as demonstrated by a reduction in plasma insulin, an improvement in whole-body glucose tolerance, an increase in insulin-stimulated glucose uptake, and Akt phosphorylation in muscle. In conclusion, FTY720 exerts beneficial effects on muscle lipid metabolism that prevent lipid accumulation and improve glucose tolerance in high fat-fed mice. Thus, FTY720 and other compounds that target sphingosine-1-phosphate signaling may have therapeutic potential in treating insulin resistance.

scholarly journals Hyperthyroidism Evokes Myocardial Ceramide Accumulation

2015 ◽  
Vol 35 (2) ◽  
pp. 755-766 ◽  
Author(s):  
Agnieszka Mikłosz ◽  
Bartłomiej Łukaszuk ◽  
Adrian Chabowski ◽  
Filip Rogowski ◽  
Krzysztof Kurek ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Cardiac Physiology ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sphingosine 1 Phosphate ◽  
Male Wistar Rats ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Cpt I ◽  
Amp Activated Protein Kinase ◽  
Ceramide Accumulation

Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T3) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). Conclusions: We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

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.

Influence of Resveratrol on Sphingolipid Metabolism in Hepatocellular Carcinoma Cells in Lipid Overload State

2019 ◽  
Vol 19 (1) ◽  
pp. 121-129
Author(s):  
Tomasz Charytoniuk ◽  
Ewa Harasim-Symbor ◽  
Agnieszka Polak ◽  
Krzysztof Drygalski ◽  
Klaudia Berk ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liquid Chromatography ◽  
High Performance ◽  
Metabolic Diseases ◽  
De Novo ◽  
Carcinoma Cells ◽  
Sphingolipid Metabolism ◽  
Gas Liquid Chromatography ◽  
Hepatocellular Carcinoma Cells ◽  
Ceramide Synthesis

Background: Obesity is characterized by increased long chain fatty acids (LCFA) uptake and impaired lipid metabolism in hepatocytes. Consequently, an enhanced intracellular lipid content, including sphingolipids, may lead to lipotoxicity. It is believed that resveratrol (RSV), one of the most extensively studied plant-derived polyphenols, and its interaction with sphingolipid metabolism may constitute one of the major therapeutic targets for cancer and metabolic diseases treatment. Objective: The aim of this study was to ascertain, whether resveratrol may affect sphingolipid metabolic pathways, enzymes and transporters in a lipid overload state. Methods: The experiments were conducted on hepatocellular carcinoma cells (HepG2) incubated with RSV and/or Palmitic Acid (PA) at the concentration of 0.5 mM and 50 µM, respectively for 16h. Intra- and extracellular sphingolipid concentrations were assessed by high-performance liquid chromatography and gas liquid chromatography. Moreover, the expression of caspase 3, selected fatty acid transporters and sphingolipid metabolism pathway proteins were estimated by Western Blot. Results: RSV alone and together with PA significantly increased the intracellular concentration of ceramide, sphinganine and sphingosine as well as the expression of enzymes related to de novo ceramide synthesis pathway. Moreover, in our study, we observed augmented ceramide and sphingomyelin efflux into the incubation media in these groups. In addition, RSV substantially reduced intracellular triacylglycerols accumulation in lipid overload conditions. Conclusion: The above-mentioned findings suggest that RSV, at least partially, demonstrates a potential protective effect on HepG2 cells in a lipid overload state.

scholarly journals Insulin Increases Ceramide Synthesis in Skeletal Muscle

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
M. E. Hansen ◽  
T. S. Tippetts ◽  
M. C. Anderson ◽  
Z. E. Holub ◽  
E. R. Moulton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Cells ◽  
Insulin Injection ◽  
Sphingolipid Metabolism ◽  
Anabolic Effect ◽  
Potential Mechanism ◽  
Ceramide Synthesis ◽  
Time Periods ◽  
Ceramide Accumulation ◽  
Novel Therapeutic

Aims. The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle.Methods. Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis.Results. In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals.Conclusions. This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.

scholarly journals Sphingosine-1-Phosphate Phosphohydrolase Regulates Endoplasmic Reticulum-to-Golgi Trafficking of Ceramide

2006 ◽  
Vol 26 (13) ◽  
pp. 5055-5069 ◽  
Author(s):  
Paola Giussani ◽  
Michael Maceyka ◽  
Hervé Le Stunff ◽  
Aki Mikami ◽  
Sandrine Lépine ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Trafficking ◽  
Fluorescent Protein ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
C Protein ◽  
Sphingosine 1 Phosphate ◽  
Green Fluorescent ◽  
Ceramide Accumulation

ABSTRACT Previous studies demonstrated that sphingosine-1-phosphate (S1P) phosphohydrolase 1 (SPP-1), which is located mainly in the endoplasmic reticulum (ER), regulates sphingolipid metabolism and apoptosis (H. Le Stunff et al., J. Cell Biol. 158:1039-1049, 2002). We show here that the treatment of SPP-1-overexpressing cells with S1P, but not with dihydro-S1P, increased all ceramide species, particularly the long-chain ceramides. This was not due to inhibition of ceramide metabolism to sphingomyelin or monohexosylceramides but rather to the inhibition of ER-to-Golgi trafficking, determined with the fluorescent ceramide analog N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-d-erythro-sphingosine (DMB-Cer). Fumonisin B1, an inhibitor of ceramide synthase, prevented S1P-induced elevation of all ceramide species and corrected the defect in ER transport of DMB-Cer, readily allowing its detection in the Golgi. In contrast, ceramide accumulation had no effect on either the trafficking or the metabolism of 6-([N-(7-nitrobenzo-2-oxa-1,3-diazol-4-yl)amino]hexanoyl)-sphingosine, which rapidly labels the Golgi even at 4°C. Protein trafficking from the ER to the Golgi, determined with vesicular stomatitis virus ts045 G protein fused to green fluorescent protein, was also inhibited in SPP-1-overexpressing cells in the presence of S1P but not in the presence of dihydro-S1P. Our results suggest that SPP-1 regulates ceramide levels in the ER and thus influences the anterograde membrane transport of both ceramide and proteins from the ER to the Golgi apparatus.

scholarly journals Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis

2002 ◽  
Vol 158 (6) ◽  
pp. 1039-1049 ◽  
Author(s):  
Hervé Le Stunff ◽  
Ismael Galve-Roperh ◽  
Courtney Peterson ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Intracellular Membranes ◽  
Sphingosine 1 Phosphate ◽  
Ceramide Accumulation ◽  
Membrane Treatment

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.

scholarly journals Vitamin K2 as a New Modulator of the Ceramide De Novo Synthesis Pathway

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3377
Author(s):  
Adrian Kołakowski ◽  
Piotr F. Kurzyna ◽  
Hubert Żywno ◽  
Wiktor Bzdęga ◽  
Ewa Harasim-Symbor ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Insulin Signaling ◽  
High Performance ◽  
De Novo ◽  
Vitamin K2 ◽  
Sphingolipid Metabolism ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
De Novo Synthesis ◽  
Expression Ratio

The aim of the study was to evaluate the influence of vitamin K2 (VK2) supplementation on the sphingolipid metabolism pathway in palmitate-induced insulin resistant hepatocytes. The study was carried out on human hepatocellular carcinoma cells (HepG2) incubated with VK2 and/or palmitic acid (PA). The concentrations of sphingolipids were measured by high-performance liquid chromatography. The expression of enzymes from the sphingolipid pathway was assessed by Western blotting. The same technique was used in order to determine changes in the expression of the proteins from the insulin signaling pathway in the cells. Simultaneous incubation of HepG2 cells with palmitate and VK2 elevated accumulation of sphinganine and ceramide with increased expression of enzymes from the ceramide de novo synthesis pathway. HepG2 treatment with palmitate and VK2 significantly decreased the insulin-stimulated expression ratio of insulin signaling proteins. Moreover, we observed that the presence of PA w VK2 increased fatty acid transport protein 2 expression. Our study showed that VK2 activated the ceramide de novo synthesis pathway, which was confirmed by the increase in enzymes expression. VK2 also intensified fatty acid uptake, ensuring substrates for sphingolipid synthesis through the de novo pathway. Furthermore, increased concentration of sphingolipids, mainly sphinganine, inhibited insulin pathway proteins phosphorylation, increasing insulin resistance development.

scholarly journals Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

2018 ◽  
Author(s):  
Gergely Karsai ◽  
Florian Kraft ◽  
Natja Haag ◽  
G Christoph Korenke ◽  
Benjamin Hänisch ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Neurological Disorder ◽  
Cell Model ◽  
Sphingolipid Metabolism ◽  
Significant Shift ◽  
Serine Palmitoyltransferase ◽  
Ceramide Synthesis ◽  
Sphingosine 1 Phosphate ◽  
Sheath Formation

Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) inDEGS1,encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-basedDEGS1knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable.AbbreviationsSLSphingolipidsSPTserine-palmitoyltransferaseCerCeramidesdhCerdihydroceramideS1Psphingosine-1-phosphateSOsphingosineHSANhereditary sensory and autonomic neuropathy

scholarly journals Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

2021 ◽  
Vol 18 (8) ◽  
pp. 4049
Author(s):  
Jukka Hintikka ◽  
Sanna Lensu ◽  
Elina Mäkinen ◽  
Sira Karvinen ◽  
Marjaana Honkanen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Aromatic Amino Acids ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Beneficial Effects ◽  
Male Wistar Rats ◽  
Branched Chain

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

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