Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: Evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction

Dekker, Mark J.; Baker, Chris; Naples, Mark; Samsoondar, Joshua P; Zhang, Rianna; Qiu, Wei; Sacco, Jennifer; Adeli, Khosrow

doi:10.1016/j.atherosclerosis.2013.01.041

Cited by 60 publications

(41 citation statements)

References 52 publications

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“…2011; Dekker et al. 2013). To assess this possibility, we employed a lipidomic approach to quantify an array of serum nonglycosylated and glycosylated ceramides in young adults consuming a diet enriched with fruit and vegetables.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

et al. 2017

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The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual's risk for type 2 diabetes, nonalcoholic fatty liver disease, low‐grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free‐living fruit and vegetable intervention on overall metabolic health, circulating ceramide supply, and inflammatory status in young adults. We discovered that adoption of the recommended DGA for fruit and vegetable intake for 8 weeks decreased waist circumference, systolic blood pressure, and circulating cholesterol. Lipidomics analysis revealed that nutritional intervention can lower circulating ceramides, including C24:0 ceramide, a known inhibitor of insulin signaling. Unexpectedly, we observed an increase in C16:0 ceramide, suggesting that this form of ceramide in circulation is not associated with metabolic disease in humans. We also observed an improved inflammatory status with enhanced fruit and vegetable intake that was correlated with ceramide concentrations. These data suggest that adopting the recommended DGA is associated with a reduction of many, but not all, ceramide species and may help to prevent or mitigate MetS. Future research needs to assess whether the ceramide‐lowering ability of nutritional intervention is associated with reduced risk of developing metabolic disease.

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Section: Resultsmentioning

confidence: 99%

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

et al. 2017

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“…Based on a number of studies examining animal models of obesity and insulin resistance, a potential link between sphingolipids and metabolic disorders has been established [32]. The consequences of genetic and pharmacological inhibition of certain steps of sphingolipid metabolism indicate that sphingolipids play a major role in the pathogenesis of insulin resistance [33-35].…”

Section: Discussionmentioning

confidence: 99%

Effects of Inhibition of Serine Palmitoyltransferase (SPT) and Sphingosine Kinase 1 (SphK1) on Palmitate Induced Insulin Resistance in L6 Myotubes

et al. 2013

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BackgroundThe objective of this study was to examine the effects of short (2 h) and prolonged (18 h) inhibition of serine palmitoyltransferase (SPT) and sphingosine kinase 1 (SphK1) on palmitate (PA) induced insulin resistance in L6 myotubes. MethodsL6 myotubes were treated simultaneously with either PA and myriocin (SPT inhibitor) or PA and Ski II (SphK1inhibitor) for different time periods (2 h and 18 h). Insulin stimulated glucose uptake was measured using radioactive isotope. Expression of insulin signaling proteins was determined using Western blot analyses. Intracellular sphingolipids content [sphinganine (SFA), ceramide (CER), sphingosine (SFO), sphingosine-1-phosphate (S1P)] were estimated by HPLC.ResultsOur results revealed that both short and prolonged time of inhibition of SPT by myriocin was sufficient to prevent ceramide accumulation and simultaneously reverse palmitate induced inhibition of insulin-stimulated glucose transport. In contrast, prolonged inhibition of SphK1 intensified the effect of PA on insulin-stimulated glucose uptake and attenuated further the activity of insulin signaling proteins (pGSK3β/GSK3β ratio) in L6 myotubes. These effects were related to the accumulation of sphingosine in palmitate treated myotubes. ConclusionMyriocin is more effective in restoration of palmitate induced insulin resistance in L6 myocytes, despite of the time of SPT inhibition, comparing to SKII (a specific SphK1 inhibitor). Observed changes in insulin signaling proteins were related to the content of specific sphingolipids, namely to the reduction of ceramide. Interestingly, inactivation of SphK1 augmented the effect of PA induced insulin resistance in L6 myotubes, which was associated with further inhibition of insulin stimulated PKB and GSK3β phosphorylation, glucose uptake and the accumulation of sphingosine.

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“…Fructose supplementation increases de novo ceramide biosynthesis and elevates ceramide concentrations in plasma [57], liver [58] and skeletal muscle [59], promoting local insulin resistance. Ceramide decreases the ability of insulin to activate Akt and GLUT4 translocation in 3T3-L1 adipocytes [60].…”

Section: Direct Dangerous Factors Under High Fructose Consumptionmentioning

confidence: 99%

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

2017

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High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.

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Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: Evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction

Cited by 60 publications

References 52 publications

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

Effects of Inhibition of Serine Palmitoyltransferase (SPT) and Sphingosine Kinase 1 (SphK1) on Palmitate Induced Insulin Resistance in L6 Myotubes

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

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