Palmitate-Induced Impairments of β-Cell Function Are Linked With Generation of Specific Ceramide Species via Acylation of Sphingosine

Manukyan, Levon; Ubhayasekera, Sarojini J.K.A.; Bergquist, Jonas; Sargsyan, Ernest; Bergsten, Peter

doi:10.1210/en.2014-1467

Cited by 62 publications

(63 citation statements)

References 34 publications

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“…Second, SPH can be acylated to ceramide via salvage synthesis pathway. It was reported that exposure of mouse pancreatic beta-cell to Palm induced the level of ceramide synthase, the enzyme of the ceramide salvage pathway, which promoted the conversion of SPH to ceramide [26]. Therefore, we speculate that inhibition of NCDase activity and stimulation of SPH converting to ceramide after Palm treatment might lead to non-obvious increase in SPH, inconsistent with the increase in ceramide.…”

Section: Discussionmentioning

confidence: 78%

Neutral ceramidase activity inhibition is involved in palmitate-induced apoptosis in INS-1 cells

Luo

Feng

et al. 2017

Endocr J

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Abstract. Neutral ceramidase (NCDase) is a class of ceramidases, a key enzyme in ceramide degradation. Recently, it was observed that NCDase activity was suppressed by saturated fatty acids to increase ceramide content in rat muscle. However, little is known about its changes in activity and roles in palmitate (Palm)-induced lipotoxicity in pancreatic β cells. Here, we demonstrated that Palm treatment significantly down-regulated NCDase activity, mRNA and protein levels in rat INS-1 cells. In addition, Palm caused a significant accumulation of ceramide, while SPH level remained unchanged, suggesting that inhibition of NCDase activity led to no change of SPH level after treatment with Palm for 24 h. Furthermore, NCDase overexpression significantly reduced Palm-induced apoptosis in INS-1 cells. Conversely, NCDase siRNA knockdown markedly exacerbated Palm-induced apoptosis. In conclusion, Palm treatment suppressed the activity of NCDase and down-regulated its mRNA and protein expression. Furthermore, NCDase inhibition was involved in Palm-induced apoptosis by blocking ceramide degradation in INS-1 cells.

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Section: Discussionmentioning

confidence: 78%

Neutral ceramidase activity inhibition is involved in palmitate-induced apoptosis in INS-1 cells

Luo

Feng

et al. 2017

Endocr J

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“…IL-6 is thought to be involved in the metabolic link between ceramide, insulin resistance and inflammation [20]. Furthermore, the accumulation of ceramide has been demonstrated to be detrimental to pancreatic beta cells [21][22][23] and may, therefore, play a direct role in the pathogenesis of type 2 diabetes. Alkenylphosphatidylethanolamines (plasmalogens) contain a vinyl ether linkage that is particularly susceptible to oxidation by reactive oxygen species, and as such they are proposed to play an antioxidant role in membranes and lipoproteins [24].…”

Section: Discussionmentioning

confidence: 99%

The prediction of type 2 diabetes in women with previous gestational diabetes mellitus using lipidomics

et al. 2015

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Aims/hypothesis The risk of developing diabetes is greater for women with previous gestational diabetes mellitus (GDM). In the general population, plasma lipidomic analysis can identify individuals at risk of developing type 2 diabetes. The aim of this study was to determine whether circulating lipid levels 12 weeks following a GDM pregnancy were associated with an increased risk of developing type 2 diabetes. Methods Plasma lipid profiles containing >300 lipids were measured in 104 normal glucose-tolerant women 12 weeks following an index GDM pregnancy using electrosprayionisation tandem mass spectrometry. Women were assessed for 10 years for development of overt type 2 diabetes. Results Among the 104 women with previous GDM, 21 (20%) developed diabetes during the median follow-up period of 8.5 years. Three lipid species, the cholesteryl ester species CE 20:4, the alkenylphosphatidylethanolamine species PE(P-36:2) and the phosphatidylserine species PS 38:4, were independently and positively associated with the development of type 2 diabetes. In a clinical model of prediction of type 2 diabetes that included age, BMI, and levels of pregnancy fasting glucose, postnatal fasting glucose, triacylglycerol and total cholesterol, the addition of these three lipid species resulted in an improvement in the net reclassification index of 22.3%. Conclusions/interpretation The lipid species CE 20:4, PE(P-36:2) and PS 38:4 were significant risk factors for the development of type 2 diabetes in women with a previous history of GDM. This report is the first to use plasma lipidomic analysis to identify individual lipids as potential biomarkers for the prediction of type 2 diabetes in women with a history of GDM.

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“…Apoptosis induced by ELOVL2 downregulation potentiated ceramide accumulation during glucolipotoxicity and was completely abolished by inhibition of de novo ceramide synthesis. Glucolipotoxicity has been shown to induce the formation of ceramides with specific N-acyl chain lengths rather than an overall increase in ceramide content [20,35]. We found that DHA blocked the accumulation of pro-apoptotic ceramide species induced by glucolipotoxicity.…”

Section: Discussionmentioning

confidence: 56%

Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets

et al. 2018

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Aims/hypothesis Dietary n-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are known to influence glucose homeostasis. We recently showed that Elovl2 expression in beta cells, which regulates synthesis of endogenous DHA, was associated with glucose tolerance and played a key role in insulin secretion. The present study aimed to examine the role of the very long chain fatty acid elongase 2 (ELOVL2)/DHA axis on the adverse effects of palmitate with high glucose, a condition defined as glucolipotoxicity, on beta cells. Methods We detected ELOVL2 in INS-1 beta cells and mouse and human islets using quantitative PCR and western blotting. Downregulation and adenoviral overexpression of Elovl2 was carried out in beta cells. Ceramide and diacylglycerol levels were determined by radio-enzymatic assay and lipidomics. Apoptosis was quantified using caspase-3 assays and poly (ADP-ribose) polymerase cleavage. Palmitate oxidation and esterification were determined by [U-14 C]palmitate labelling. Results We found that glucolipotoxicity decreased ELOVL2 content in rodent and human beta cells. Downregulation of ELOVL2 drastically potentiated beta cell apoptosis induced by glucolipotoxicity, whereas adenoviral Elovl2 overexpression and supplementation with DHA partially inhibited glucolipotoxicity-induced cell death in rodent and human beta cells. Inhibition of beta cell apoptosis by the ELOVL2/DHA axis was associated with a decrease in ceramide accumulation. However, the ELOVL2/DHA axis was unable to directly alter ceramide synthesis or metabolism. By contrast, DHA increased palmitate oxidation but did not affect its esterification. Pharmacological inhibition of AMP-activated protein kinase and etomoxir, an inhibitor of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme in fatty acid β-oxidation, attenuated the protective effect of the ELOVL2/DHA axis during glucolipotoxicity. Downregulation of CPT1 also counteracted the anti-apoptotic action of the ELOVL2/DHA axis. By contrast, a mutated active form of Cpt1 inhibited glucolipotoxicity-induced beta cell apoptosis when ELOVL2 was downregulated. Conclusions/interpretation Our results identify ELOVL2 as a critical pro-survival enzyme for preventing beta cell death and dysfunction induced by glucolipotoxicity, notably by favouring palmitate oxidation in mitochondria through a CPT1-dependent mechanism.

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Palmitate-Induced Impairments of β-Cell Function Are Linked With Generation of Specific Ceramide Species via Acylation of Sphingosine

Cited by 62 publications

References 34 publications

Neutral ceramidase activity inhibition is involved in palmitate-induced apoptosis in INS-1 cells

Neutral ceramidase activity inhibition is involved in palmitate-induced apoptosis in INS-1 cells

The prediction of type 2 diabetes in women with previous gestational diabetes mellitus using lipidomics

Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets

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