Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress

Verma, Mahesh Kumar; Yateesh, Aggunda Nagaraju; Neelima, Korrapati; Pawar, Niketa; Sandhya, Kandoor; Poornima, Jayaram; Lakshmi, Mudigere N; Yogeshwari, Sivakumaran; Pallavi, Puttrevana M; Oommen, Anup Mammen; Somesh, Baggavalli P; Jagannath, Madanahalli R

doi:10.1186/2193-1801-3-255

Cited by 14 publications

(15 citation statements)

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“…Increased sphingomyelinase activity generates ceramide and has been reported in insulinresistant liver [38] and in skeletal muscle from insulinresistant (vs insulin-sensitive) obese humans [39]. Further, inhibition of sphingomyelinase prevented saturated fat induced insulin resistance in skeletal muscle myotubes [40]. These data make sphingomyelinase a likely candidate to explain increased C18:0 ceramide species in skeletal muscle.…”

Section: Discussionmentioning

confidence: 71%

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans

et al. 2016

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Aims/hypotheses Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise. Methods We measured basal relationships and the effect of acute exercise (1.5 h at 50% V ⋅ O 2max ) and recovery on muscle sphingolipid content in obese volunteers, endurance trained athletes and individuals with type 2 diabetes. Results Muscle C18:0 ceramide (p = 0.029), dihydroceramide (p = 0.06) and glucosylceramide (p = 0.03) species were inversely related to insulin sensitivity without differences in total ceramide, dihydroceramide, and glucosylceramide concentration. Muscle C18:0 dihydroceramide correlated with markers of muscle inflammation (p = 0.04). Transcription of genes encoding sphingolipid synthesis enzymes was higher in athletes, suggesting an increased capacity for sphingolipid synthesis. The total concentration of muscle ceramides and sphingolipids increased during exercise and then decreased after recovery, during which time ceramide levels reduced to significantly below basal levels.Conclusions/interpretation These data suggest ceramide and other sphingolipids containing stearate (18:0) are uniquely related to insulin resistance in skeletal muscle. Recovery from an exercise bout decreased muscle ceramide concentration; this may represent a mechanism promoting the insulinsensitising effects of acute exercise.

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Section: Discussionmentioning

confidence: 71%

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans

et al. 2016

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“…In glioma cells, superoxide promotes ceramide formation through activation of neutral sphingomyelinase [ 229 ]. Sphingomyelinase inhibition reduces intramyocellular ceramide and protects muscle cells from insulin resistance [ 230 , 231 ].…”

Section: Mechanisms Of the Inhibition Of Insulin Signaling By Cellmentioning

confidence: 99%

Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance

Onyango

2018

Oxidative Medicine and Cellular Longevity

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Insulin resistance (IR), a key component of the metabolic syndrome, precedes the development of diabetes, cardiovascular disease, and Alzheimer's disease. Its etiological pathways are not well defined, although many contributory mechanisms have been established. This article summarizes such mechanisms into the hypothesis that factors like nutrient overload, physical inactivity, hypoxia, psychological stress, and environmental pollutants induce a network of cellular stresses, stress responses, and stress response dysregulations that jointly inhibit insulin signaling in insulin target cells including endothelial cells, hepatocytes, myocytes, hypothalamic neurons, and adipocytes. The insulin resistance-inducing cellular stresses include oxidative, nitrosative, carbonyl/electrophilic, genotoxic, and endoplasmic reticulum stresses; the stress responses include the ubiquitin-proteasome pathway, the DNA damage response, the unfolded protein response, apoptosis, inflammasome activation, and pyroptosis, while the dysregulated responses include the heat shock response, autophagy, and nuclear factor erythroid-2-related factor 2 signaling. Insulin target cells also produce metabolites that exacerbate cellular stress generation both locally and systemically, partly through recruitment and activation of myeloid cells which sustain a state of chronic inflammation. Thus, insulin resistance may be prevented or attenuated by multiple approaches targeting the different cellular stresses and stress responses.

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“…Additionally, ceramide-induced PKC ζ activation triggered the inhibitory phosphorylation of Akt [ 66 ]. Inhibition of nSMase, which should decrease ceramide generation, abolished palmitate-induced JNK and NF- κ B activation and ER stress, conferring improvement in insulin resistance [ 67 ]. Furthermore, ceramide has also been implicated in the regulation of ectopic lipid accumulation in skeletal muscle and aggravation of insulin resistance [ 21 , 68 ].…”

Section: Sphingolipids In Hfd-induced Pathobiologymentioning

confidence: 99%

Sphingolipids in High Fat Diet and Obesity‐Related Diseases

Choi

Snider

2015

Mediators of Inflammation

114

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Nutrient oversupply associated with a high fat diet (HFD) significantly alters cellular metabolism, and specifically including sphingolipid metabolism. Sphingolipids are emerging as bioactive lipids that play key roles in regulating functions, in addition to their traditional roles as membrane structure. HFD enhances de novo sphingolipid synthesis and turnover of sphingolipids via the salvage pathway, resulting in the generation of ceramide, and more specifically long chain ceramide species. Additionally, HFD elevates sphingomyelin and sphingosine-1 phosphate (S1P) levels in several tissues including liver, skeletal muscle, adipose tissue, and cardiovascular tissues. HFD-stimulated sphingolipid generation contributes to systemic insulin resistance, dysregulated lipid accumulation, and cytokine expression and secretion from skeletal muscle and adipose tissues, exacerbating obesity-related conditions. Furthermore, altered sphingolipid levels, particularly ceramide and sphingomyelin, are involved in obesity-induced endothelial dysfunction and atherosclerosis. In this review, HFD-mediated sphingolipid metabolism and its impact on HFD-induced biology and pathobiology will be discussed.

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Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress

Cited by 14 publications

References 64 publications

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans

Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance

Sphingolipids in High Fat Diet and Obesity‐Related Diseases

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