Dihydroceramide-based Response to Hypoxia

Devlin, Cecilia M.; Lahm, Tim; Hubbard, Walter C.; Demark, Mary Van; Wang, Kevin C.; Wu, Xue; Bielawska, Alicja; Obeid, Lina M.; Ivan, Mircea; Petrache, Irina

doi:10.1074/jbc.m111.297994

Cited by 64 publications

(39 citation statements)

References 40 publications

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“…Alternatively, other factors might contribute to decrease of DEGS activity in cells. Previous studies have reported that oxidative stress compromises DEGS activity, including hydrogen peroxide [19], hypoxic environment [39] and depletion of GSH [19]. However, we found that NAC, which helps reserve GSH, did not reverse γTE-induced modulation of sphingolipids or cell death (data not shown), suggesting that oxidative stress may not play a major role in γTE-mediated sphingolipid modulation.…”

Section: Discussioncontrasting

confidence: 61%

Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment

Jang

Rao

Jiang

2017

The Journal of Nutritional Biochemistry

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Vitamin E gamma-tocotrienol (γTE) is known to have anticancer effects, but mechanisms underlying these actions are not clear. Here using liquid chromatography tandem mass spectrometry, we show that γTE induced marked changes of sphingolipids including rapid elevation of dihydrosphingosine and dihydroceramides (dhCers) in various types of cancer cells. The elevation of dihydrosphingolipids coincided with increased cellular stress, as indicated by JNK phosphorylation, and was prior to any sign of induction of apoptosis. Chemically blocking de novo synthesis of sphingolipids partially counteracted γTE-induced apoptosis and autophagy. Experiments using 13C3, N-labeled L-serine together with enzyme assays indicate that γTE inhibited cellular dihydroceramide desaturase (DEGS) activity without affecting its protein expression or de novo synthesis of sphingolipids. Unlike the effect on dhCers, γTE decreased ceramides (Cers) after 8 h treatment, but increased C18:0-Cer and C16:0-Cer after 16 and 24 h, respectively. The increase of Cers coincides with γTE-induced apoptosis and autophagy. Since γTE inhibits DEGS and decreases de novo Cer synthesis, elevation of Cers during prolonged γTE treatment is likely caused by sphingomeylinase-mediated hydrolysis of sphingomyelin. This idea is supported by the observation that an acid sphingomeylinase inhibitor partially reversed γTE-induced cell death. Our study demonstrates that γTE altered sphingolipid metabolism by inhibiting DEGS activity and possibly by activating SM hydrolysis during prolonged treatment in cancer cells.

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Section: Discussioncontrasting

confidence: 61%

Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment

Jang

Rao

Jiang

2017

The Journal of Nutritional Biochemistry

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“…It has recently been shown by lipid analysis that restricting oxygen to the brain leads to inhibition of dihydroceramide desaturase and the accumulation of dihydroceramides, dihydrosphingomyelins and dihydroglycosylceramides [42,43]. DHC is also seen in Hemorrhagic stroke [37] and this evidence of hypoxic injury to brain and can be detected by both HPTLC and HPLC/MS/MS (Fig.13).…”

Section: Methods For Measuring Specific Brain Lipidsmentioning

confidence: 92%

“…DHC is also seen in Hemorrhagic stroke [37] and this evidence of hypoxic injury to brain and can be detected by both HPTLC and HPLC/MS/MS (Fig.13). They have a separate metabolic pathway from the more bioactive ceramides and S1P (Fig 13]) [42,43] and in fact little is known of the biological function of dihydrosphingosines. A myco-toxin found in corn (Fumonisin B1) inhibits de novo synthesis of sphingolipids and leads to increases in dihydrosphingosine and deoxysphingolipids, which may be responsible for some of the brain-specific brain structural deficits observed in different animals.…”

Section: Methods For Measuring Specific Brain Lipidsmentioning

confidence: 99%

Measuring brain lipids

Dawson

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The rapid development of analytical technology has made lipidomics an exciting new area and this review will focus more on modern approaches to lipidomics than on earlier technology. Although not fully comprehensive for all possible brain lipids, the intent is to at least provide a reference for the analysis of classes of lipids found in brain and nervous tissue. We will discuss problems posed by the brain because of its structural and functional heterogeneity, the development changes it undergoes (myelination, aging, pathology etc.) and its cellular heterogeneity (neurons, glia etc). Section 2 will discuss the various ways in which brain tissue can be extracted to yield lipids for analysis and Section 3 will cover a wide range of techniques used to analyze brain lipids such as chromatography and mass-spectrometry. In Section 4 we will discuss ways of analyzing some of the specific biologically active brain lipids found in very small amounts except in pathological conditions and section 5 looks to the future of experimental lipidomic modification in the brain.

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“…6 However, although de novo sphingolipid synthesis may be enhanced in the post-ischemic heart, our results from heart biopsies and cardiomyocytes indicate that ischemia/hypoxia-induced cardiac ceramide accumulation is independent of the sphingolipid de novo synthesis pathway but instead results from hydrolysis of sphingomyelin catalyzed by acid sphingomyelinase. Indeed, it is known that the enzyme catalyzing ceramide synthesis from dihydroceramides is oxygen dependent, 7 and thus it is unlikely that de novo synthesis of ceramides would occur in ischemic tissue. 8 Targeting acid sphingomyelinase in the heart would represent a novel approach to reduce cardiac ceramide accumulation.…”

Section: Discussionmentioning

confidence: 99%

Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart

Klevstig

Ståhlman

Lundqvist

et al. 2016

Journal of Molecular and Cellular Cardiology

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Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1+/- mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1+/- mice 24 h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.

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Dihydroceramide-based Response to Hypoxia

Cited by 64 publications

References 40 publications

Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment

Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment

Measuring brain lipids

Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart

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