1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma

Duan, Jingjing; Merrill, Alfred H.

doi:10.1074/jbc.r115.658823

Cited by 79 publications

(93 citation statements)

References 97 publications

(131 reference statements)

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“…Because of their only recent identification in humans, very little is known about effects and functions of deoxySLs (49). In this study, we addressed some fundamental questions about the cellular metabolism and localization of de-oxySLs, potentially leading to novel insights about their pathomechanism in diseases like diabetic neuropathy and HSAN1.…”

Section: Discussionmentioning

confidence: 99%

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Alecu

Tedeschi

Behler

et al. 2017

Journal of Lipid Research

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1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs. Our results indicate that the metabolism of these lipids is restricted to only some lipid species and that they are not converted to canonical sphingolipids or fatty acids. Furthermore, exogenously added alkyne-doxSA [(2S,3R)-2-aminooctadec-17-yn-3-ol] localized to mitochondria, causing mitochondrial fragmentation and dysfunction. The induced mitochondrial toxicity was also shown for natural doxSA, but not for sphinganine, and was rescued by inhibition of ceramide synthase activity. Our findings therefore indicate that mitochondrial enrichment of an N-acylated doxSA metabolite may contribute to the neurotoxicity seen in diabetic neuropathy and HSAN1. Hence, we provide a potential explanation for the characteristic vulnerability of peripheral nerves to elevated levels of deoxySLs.

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Section: Discussionmentioning

confidence: 99%

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Alecu

Tedeschi

Behler

et al. 2017

Journal of Lipid Research

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“…The conjugation of L-alanine forms the DSL deoxy-sphinganine; when glycine is used in the reaction, deoxy-methylsphinganine is formed (Rotthier et al 2010). Because both of these sphingolipid metabolites do not contain the hydroxyl group normally located at C-1 in the sphinganine molecule formed when L-serine is used in the reaction catalyzed by SPT, these modified sphingolipids cannot be further metabolized to the more complex sphingolipids nor can they be degraded via the normal physiologic sphingolipid catabolic pathways to form 1-phosphate derivatives (Duan and Merrill 2015). Analysis of DSL in plasma revealed that DSL are present at low levels in plasma from normal, healthy individuals, primarily in very low density and low-density lipoproteins (Bertea et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Hammad

Baker²,

Abiad

et al. 2016

Neuromol Med

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Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ≥4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy.

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“…The configuration of some asymmetric carbons in SPLs were assigned based on the de novo SPL biosynthetic pathway reported in the reference (Supplementary Figure S3). As a fungi, possible SPLs synthesis process of Cordyceps may involve a de novo SPL biosynthetic pathway in all eukaryotic cells161718, metabolism of fungi phytosphingolipid1920, as well as biosynthetic pathway of non-traditional 1-deoxysphingoid bases2122. These publications reported common sphingolipids metabolism existing in all eukaryotic cells and special biosynthetic pathway of sphingolipids in fungi, which provided important evidence to describe the plausible biosynthetic pathway of sphingolipids in Cordyceps.…”

Section: Resultsmentioning

confidence: 79%

New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

Han

et al. 2016

Sci Rep

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A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

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1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma

Cited by 79 publications

References 97 publications

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

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