Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Zabielski, Piotr; Błachnio-Zabielska, Agnieszka; Lanza, Ian R.; Gopala, Srinivas; Manjunatha, S; Jakaitis, Daniel R.; Persson, Xuan-Mai; Gransee, Jaime; Klaus, Katherine A.; Schimke, Jill M.; Jensen, Michael D.; Nair, K. Sreekumaran

doi:10.1152/ajpendo.00610.2012

Cited by 28 publications

(26 citation statements)

References 83 publications

(84 reference statements)

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“…In a previous study using a rodent model of type 1 diabetes, elevated FFA increased the ceramide contents in skeletal muscle subcellular compartments compared with a control condition (30). However, the plasma FFA concentrations >2 mmol/L resulting from insulin deprivation were likely a greater stimulus to de novo ceramide synthesis compared with the control condition than the narrower range of FFA concentrations in our study.…”

Section: Discussionmentioning

confidence: 90%

Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans

et al. 2017

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We investigated the relationship between insulin resistance markers and subsarcolemmal (SS) and intramyofibrillar (IMF) ceramide concentrations, as well as the contribution of plasma palmitate (6.5-h infusion of [U-13C]palmitate) to intramyocellular ceramides. Seventy-six postabsorptive men and women had muscle biopsies 1.5, 6.5, and 24 h after starting the tracer infusion. Concentrations and enrichment of muscle ceramides were measured by liquid chromatography-tandem mass spectrometry. We found that HOMA of insulin resistance, plasma insulin, and triglyceride concentrations were positively correlated with SS C16:0 and C18:1 ceramide, but not SS C14:0-Cer, C20:0-Cer, C24:0-Cer, and C24:1-Cer concentrations; IMF ceramide concentrations were not correlated with any metabolic parameters. The fractional contribution of plasma palmitate to 16:0 ceramide was greater in SS than IMF (SS, 18.2% vs. IMF, 8.7%; P = 0.0006). Plasma insulin concentrations correlated positively with the fractional contribution of plasma palmitate to SS 16:0 ceramide. The fractional contribution of plasma palmitate to intramyocellular SS 16:0 ceramide was positively correlated with SS C16:0 ceramide concentrations (γ = 0.435; P = 0.002). We conclude that skeletal muscle SS ceramides, especially C16 to C18 chain lengths and the de novo synthesis of intramyocellular ceramide from plasma palmitate are associated with markers of insulin resistance.

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Section: Discussionmentioning

confidence: 90%

Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans

et al. 2017

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“…Only C18:0-Cer and C18:1-Cer species were elevated whereas C16:0-Cer remained stable. Recent studies link C16:0-Cer with hepatic insulin resistance [49,50] whereas skeletal muscle C18-derived ceramides account for majority of Cer accumulation in HFD animals [51], mice with uncontrolled STZ-diabetes [52] and in obese, diabetic patients [53]. Inhibition of de novo sphingolipid synthesis by myriocin also had greatest impact on C18:0-and C18:1-Cer species and was accompanied by significant improvement in both the whole-body and skeletal muscle insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Błachnio-Zabielska

Chacińska

Vendelbo

et al. 2016

Cell Physiol Biochem

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Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U¹³C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

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“…FFA transporters, CD36 and FATP1, in sarcolemma ( 2,73 ). This facilitates the transport of FFAs into cytosol where they are rapidly converted to acyl-CoAs, thus raising their levels ( 69 ). Acyl-CoAs are immediate substrates for SPT and CerS, which are the critical enzymes in ceramide formation by the de novo pathway ( Fig.…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

“…Elevated levels of FFA contribute to increased ceramide formation (64)(65)(66). In STZ-induced diabetes, the lack of insulin releases suppression of lipolysis in adipocytes ( 67,68 ), resulting in elevated levels of FFA in plasma (69)(70)(71)(72), accompanied by expression of is not in direct equilibrium with the pool of ceramide accessible to NCDase, and that the increase in SM in mitochondrial subpopulations of diabetic hearts refl ects a suppression of SM hydrolysis rather than activation of SM synthesis. In line with this notion, there is no evidence of the SM synthase presence in mitochondria, but a novel mitochondria-associated neutral SMase has been cloned and characterized ( 12,13,83 ).…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Cited by 28 publications

References 83 publications

Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans

Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

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