Alteration in sphingolipid metabolism: bioassays for fumonisin- and ISP-I-like activity in tissues, cells and other matrices

Riley, Ronald T.; Norred, William P.; Wang, E.; Merrill, Alfred H.

doi:10.1002/1522-7189(199911/12)7:6<407::aid-nt84>3.0.co;2-0

Cited by 32 publications

(29 citation statements)

References 20 publications

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“…To obtain sufficient quantity of the unidentified sphingoid base for chemical characterization, the free sphingoid bases were partially purified from thirty 75-cm 2 flasks of confluent cultures of LLC-PK 1 cells that had been treated with 35 M FB 1 for 120 h. The cells were scraped and pooled in a single glass tube, and the free sphingoid bases were extracted and treated with 0.1 M KOH in methanol to decrease interference from glycerolipids as described by Riley et al (26). The extracted sphingoid bases were dissolved in a small volume of acetonitrile:H 2 O:formic acid (49.5:49.5:1, v/v/v) and loaded on a minicolumn of preparative C18 packing material (5 mm ϫ 60 mm) equilibrated with the same mobile phase.…”

Section: Methodsmentioning

confidence: 99%

“…Panel B shows the reversibility of these elevations when LLC-PK 1 cells were exposed for 48 h to FB 1 followed by a change to fresh medium without FB 1 (at time 0) but with (black circles and squares) or without myriocin (white circles and squares). The free sphingoid bases were analyzed by HPLC with fluorescence detection of the free sphingoid bases as OPA derivatives using C20-Sa (d20:0) as an internal standard (26). The data are the mean Ϯ S.D.…”

Section: Biosynthesis Of 1-deoxysa From [ 13 C]alanine By Spt-becausementioning

confidence: 99%

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Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Zitomer

Mitchell

Voss

et al. 2009

Journal of Biological Chemistry

216

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13 C]deoxySa. 1-DeoxySa was elevated in FB 1 -treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK 1 and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB 1 , substantial amounts of 1-deoxySa are made and acylated to N-acyl-1-deoxySa (i.e. 1-deoxydihydroceramides). Thus, these compounds are an underappreciated category of bioactive sphingoid bases and "ceramides" that might play important roles in cell regulation. Fumonisins (FB)2 cause diseases of horses, swine, and other farm animals and are regarded to be potential risk factors for human esophageal cancer (1) and, more recently, birth defects (2). Studies of this family of mycotoxins, and particularly of the highly prevalent subspecies fumonisin B 1 (FB 1 ) (reviewed in Refs. 1 and 2), have established that FB 1, is both toxic and carcinogenic for laboratory animals, with the liver and kidney being the most sensitive target organs (3, 4). Other FB are also toxic, but their carcinogenicity is unknown.FB are potent inhibitors of ceramide synthase(s) (CerS) (5), the enzymes responsible for acylation of sphingoid bases using fatty acyl-CoA for sphingolipid biosynthesis de novo and recycling pathways (6). As a consequence of this inhibition, the substrates sphinganine (Sa) and, usually to a lesser extent, sphingosine (So), accumulate and are often diverted to sphinganine 1-phosphate (Sa1P) and sphingosine 1-phosphate (S1P), respectively (7), while the product N-acylsphinganines (dihydroceramides), N-acylsphingosines (ceramides, Cer), and more complex sphingolipids decrease (5, 7). This disruption of sphingolipid metabolism has been proposed to be responsible for the toxicity, and possibly carcinogenicity, of FB, based on mechanistic studies with cells in culture (5,(7)(8)(9). This has been borne out by a number of animal feeding studies that have correlated the elevation of Sa in blood, urine, liver, and kidney with liver and kidney toxicity (4, 7, 10, 11).Most of the mechanistic studies have focused on the accumulation of free Sa and other sphingoid bases, because these compounds are highly cytotoxic, although the large number of bioactive metabolites in this pathway make it likely that multi-

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Section: Methodsmentioning

confidence: 99%

Section: Biosynthesis Of 1-deoxysa From [ 13 C]alanine By Spt-becausementioning

confidence: 99%

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Zitomer

Mitchell

Voss

et al. 2009

Journal of Biological Chemistry

216

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“…To pellet precipitated protein, samples were centrifuged at 16,000 g for 5 min and the supernatant was transferred to a new tube. Lipids were acid/base hydrolyzed to remove the N-acyl chain, as described earlier (4,23).…”

Section: Extraction and Analysis Of Sphingoid And Deoxysphingoid Basesmentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

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“…The lipids were analysed as described before [15,21]. Tissue samples were homogenised in lysis buffer (25 mmol/l HEPES pH 8, 0.2% Triton X-100 [vol./vol.])…”

Section: Quantification Of Sphingoid Basesmentioning

confidence: 99%

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

et al. 2011

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Aims/hypothesis Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C 12 to C 18 ) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes.Methods We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n=25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. Results Deoxysphingolipids (dSLs) were significantly elevated (p ¼ 5 Â 10 À6 ) in patients with the metabolic syndrome (0.11±0.04 μmol/l) compared with controls (0.06±0.02 μmol/l) but did not differ between the metabolic A. Othman and M. F. Rütti contributed equally to this study. Diabetologia (2012) 55:421-431 DOI 10.1007/s00125-011-2384 syndrome and diabetes groups. Levels of C 16 -sphingosinebased sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p=0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. Conclusions/interpretation We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

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Alteration in sphingolipid metabolism: bioassays for fumonisin- and ISP-I-like activity in tissues, cells and other matrices

Cited by 32 publications

References 20 publications

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

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