Histological analyses by matrix-assisted laser desorption/ionization-imaging mass spectrometry reveal differential localization of sphingomyelin molecular species regulated by particular ceramide synthase in mouse brains

Sugimoto, Masayuki; Shimizu, Yoichi; Yoshioka, Takeshi; Wakabayashi, Masato; Tanaka, Yukari; Higashino, Kenichi; Numata, Yoshito; Sakaï, Shota; Kihara, Akio; Igarashi, Yasuyuki; Kuge, Yuji

doi:10.1016/j.bbalip.2015.09.004

Cited by 27 publications

(23 citation statements)

References 56 publications

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“…In particular, Fourier transform ion cyclotron resonance-mass spectrometry (FTICR-MS) was used to specifically identify the exact mass and isotopic distribution of target molecules using ultra-high-mass resolution (>500,000) and structural analysis with an MS/MS approach [ 10 , 11 ]. Thus, MALDI-FTICR-IMS can clearly visualize several target molecules as independent images [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Part of the Cers is transferred from the endoplasmic reticulum to the Golgi apparatus by a Cer transport protein, and is then converted to SM by the transfer of phosphocholine from phosphatidylcholine through SM synthase (SMS) [ 16 , 17 ]. We and others have independently reported that the distribution of SMs in the mouse brain differed with the lengths of their acyl-chain [ 12 , 18 ]. For example, C18-SMs were localized in cell body-rich gray matter, while C24-SMs were located in myelin-rich white matter.…”

Section: Introductionmentioning

confidence: 99%

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Imaging Mass Spectrometry Reveals Acyl-Chain- and Region-Specific Sphingolipid Metabolism in the Kidneys of Sphingomyelin Synthase 2-Deficient Mice

et al. 2016

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Obesity was reported to cause kidney injury by excessive accumulation of sphingolipids such as sphingomyelin and ceramide. Sphingomyelin synthase 2 (SMS2) is an important enzyme for hepatic sphingolipid homeostasis and its dysfunction is considered to result in fatty liver disease. The expression of SMS2 is also high in the kidneys. However, the contribution of SMS2 on renal sphingolipid metabolism remains unclear. Imaging mass spectrometry is a powerful tool to visualize the distribution and provide quantitative data on lipids in tissue sections. Thus, in this study, we analyzed the effects of SMS2 deficiency on the distribution and concentration of sphingomyelins in the liver and kidneys of mice fed with a normal-diet or a high-fat-diet using imaging mass spectrometry and liquid chromatography/electrospray ionization-tandem mass spectrometry. Our study revealed that high-fat-diet increased C18–C22 sphingomyelins, but decreased C24-sphingomyelins, in the liver and kidneys of wild-type mice. By contrast, SMS2 deficiency decreased C18–C24 sphingomyelins in the liver. Although a similar trend was observed in the whole-kidneys, the effects were minor. Interestingly, imaging mass spectrometry revealed that sphingomyelin localization was specific to each acyl-chain length in the kidneys. Further, SMS2 deficiency mainly decreased C22-sphingomyelin in the renal medulla and C24-sphingomyelins in the renal cortex. Thus, imaging mass spectrometry can provide visual assessment of the contribution of SMS2 on acyl-chain- and region-specific sphingomyelin metabolism in the kidneys.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Imaging Mass Spectrometry Reveals Acyl-Chain- and Region-Specific Sphingolipid Metabolism in the Kidneys of Sphingomyelin Synthase 2-Deficient Mice

et al. 2016

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“…In the mouse brain, all Cers genes but Cers3 are expressed (37). Brain sphingolipids consist mainly of C18 and C24 acyl-chains: Cers1 synthesizes C18-Cer in neurons, whereas Cers2 synthesizes C24-ceramides in oligodendrocytes (37,38). Phosphorylation sites in the C-terminal regions are mostly conserved between mouse Cers2-6 and human CERS2-6 (Fig.…”

Section: Primermentioning

confidence: 99%

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Sassa

Hirayama

Kihara

2016

Journal of Biological Chemistry

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Ceramide and complex sphingolipids regulate important cellular functions including cell growth, apoptosis, and signaling. Dysregulation of sphingolipid metabolism leads to pathological consequences such as sphingolipidoses and insulin resistance. Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. In the present study, we demonstrated that CERS2-6 were phosphorylated at the cytoplasmic C-terminal regions. Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing its V max value. Phosphorylation modestly increased the catalytic activities of CERS4 and -5 and mildly increased those of CERS3 and -6. Dephosphorylation of endogenous ceramide synthases in the mouse brain led to severely reduced activity toward the Cers2 substrates C22:0/C24:0-CoAs and modestly reduced activity toward the Cers5/6 substrate C16:0-CoA. These results suggest that the phosphorylation of ceramide synthases may be a key regulatory point in the control of the distribution and levels of sphingolipids of various acyl-chain lengths.Sphingolipids, one of the major lipid constituents of eukaryotic membranes, mediate a number of cellular and physiological functions such as cell growth, apoptosis, immune responses, and the epidermal permeability barrier, whereas their abnormal metabolism is involved in diseases such as sphingolipidoses, neural disorders, and diabetes (1-7). Ceramides are located in the hub of sphingolipid metabolism. Ceramides are precursors for complex sphingolipids, whereas their hydrolysis releases a sphingoid long-chain base and a fatty acid (FA).2 The released long-chain base can then be recycled to synthesize new ceramide, or metabolized further into other lipids such as sphingosine 1-phosphate (8 -10). Ceramide synthases catalyze the formation of an amide bond between the long-chain base and the FA in the endoplasmic reticulum. In most tissues, the chain lengths of the FA moieties of ceramides are C16 -

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“…Indeed, novel lipid biomarkers, which are useful for the prediction of Alzheimer's disease, were discovered using global lipid analysis . We constructed a global analytical system for glycerolipids, glycerophospholipids, and sphingolipids (Supplementary Table S1, Supporting Information), and this system has already been applied to investigate the role of some lipids in the development of obesity . However, there has been little application of high‐resolution MS to globally analyze oxidized fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…[36] We constructed a global analytical system for glycerolipids, glycerophospholipids, and sphingolipids ( Supplementary Table S1, Supporting Information), and this system has already been applied to investigate the role of some lipids in the development of obesity. [37] However, there has been little application of high-resolution MS to globally analyze oxidized fatty acids. In this study, for the purpose of the discovery and identification of unknown lipid metabolites in biological samples, a global analytical system was constructed for oxidized fatty acids using mouse lung as the model tissue.…”

Section: Discussionmentioning

confidence: 99%

A hybrid strategy using global analysis of oxidized fatty acids and bioconversion by Bacillus circulans

Sanaki

Inaba

Fujiwara

et al. 2016

Rapid Comm Mass Spectrometry

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Histological analyses by matrix-assisted laser desorption/ionization-imaging mass spectrometry reveal differential localization of sphingomyelin molecular species regulated by particular ceramide synthase in mouse brains

Cited by 27 publications

References 56 publications

Imaging Mass Spectrometry Reveals Acyl-Chain- and Region-Specific Sphingolipid Metabolism in the Kidneys of Sphingomyelin Synthase 2-Deficient Mice

Imaging Mass Spectrometry Reveals Acyl-Chain- and Region-Specific Sphingolipid Metabolism in the Kidneys of Sphingomyelin Synthase 2-Deficient Mice

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

A hybrid strategy using global analysis of oxidized fatty acids and bioconversion by Bacillus circulans

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