Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?

Othman, Alaa; Benghozi, Renée; Alecu, Irina; Yu, Wengong; Niesor, Eric J.; Eckardstein, Arnold von; Hornemann, Thorsten

doi:10.1016/j.jacl.2015.03.011

Cited by 36 publications

(27 citation statements)

References 42 publications

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“…The activity of CYP4A and CYP4F enzymes can be enhanced by peroxisome proliferators like fibrates (27,28), and fenofibrate has been shown to lower 1-deoxySA and 14,15-cisdeoxySO levels in the plasma of dyslipidemic patients (29). Thus, we inferred that CYP4A or CYP4F could potentially be involved in the downstream metabolism of 1-deoxySLs.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 85%

“…We hypothesized that CYP enzymes could be involved in the downstream metabolism of 1-deoxySLs, as these enzymes are hydroxylases of both endogenous and exogenous substrates. In particular, we considered the CYP4A and CYP4F sub-families, which are involved in fatty acid hydroxylation, as their activity is enhanced by peroxisome proliferators like fibrates (27,28), and fenofibrate has been shown to lower 1-deoxySA and 14,15-cis-deoxySO levels in the plasma of dyslipidemic patients (29). Thus, we inferred that members of the CYP4A or CYP4F subfamilies could be involved in the downstream metabolism of 1-deoxySLs.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 99%

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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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Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 85%

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

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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“…The SPH m18:1(E)(3OH) standards (5E, 8E, 12E, 13E, and 14E) were synthesized based on an unpublished method that will be issued elsewhere. An LC-MS method described previously (8) was used to compare retention times and in-source fragmentation. Sphingoid bases were separated by RPLC on a C18-column (Uptisphere 120 Å, 5 m, 125 × 2 mm; Interchim, Montluçon, France) and analyzed on a TSQ Quantum Ultra or a Q Exactive (Thermo, Reinach BL, Switzerland) using an atmospheric pressure chemical ionization (APCI) interface.…”

Section: Lc-ms Methodsmentioning

confidence: 99%

“…Cells were harvested after 24 h and the whole sphingolipid extract was hydrolyzed to get the free sphingoid bases, as described previously with some modifications (7,8). The cell pellet was dissolved in 100 l of PBS.…”

Section: Cell Extractmentioning

confidence: 99%

Elucidating the chemical structure of native 1-deoxysphingosine

Steiner

Saied

Othman

et al. 2016

Journal of Lipid Research

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Sphingolipids are typically formed by the condensation of serine and palmitoyl-CoA, a reaction catalyzed by the serine-palmitoyltransferase (SPT) enzyme. Besides these canonical substrates, SPT can use other acyl-CoAs, but also alanine or glycine, as substrates, which then form a category of atypical 1-deoxysphingolipids (1-deoxySLs) that lack the C1-OH group of canonical sphingolipids (1, 2).Several missense mutations in SPT, which are associated with the rare inherited neuropathy, HSAN1, induce a permanent shift in the substrate specificity of the enzyme resulting in increased 1-deoxySL formation. HSAN1 is a rare autosomal and dominantly inherited axonopathy and is clinically characterized by a progressive loss of pain and Abstract The 1-deoxysphingolipids (1-deoxySLs) are formed by an alternate substrate usage of the enzyme, serine-palmitoyltransferase, and are devoid of the C1-OHgroup present in canonical sphingolipids. Pathologically elevated 1-deoxySL levels are associated with the rare inherited neuropathy, HSAN1, and diabetes type 2 and might contribute to  cell failure and the diabetic sensory neuropathy. In analogy to canonical sphingolipids, it was assumed that 1-deoxySLs also bear a (4E) double bond, which is normally introduced by sphingolipid delta(4)-desaturase 1. This, however, was never confirmed. We therefore supplemented HEK293 cells with isotope-labeled D 3 -1-deoxysphinganine and compared the downstream formed D 3 -1-deoxysphingosine (1-deoxySO) to a commercial synthetic SPH m18:1(4E)(3OH) standard. Both compounds showed the same m/z, but differed in their RPLC retention time and atmospheric pressure chemical ionization in-source fragmentation, suggesting that the two compounds are structural isomers. Using dimethyl disulfide derivatization followed by MS 2 as well as differential-mobility spectrometry combined with ozone-induced dissociation MS, we identified the carbon-carbon double bond in native 1-deoxySO to be located at the (14) position. Comparing the chromatographic behavior of native 1-deoxySO to chemically synthesized SPH m18:1(14Z) and (14E) stereoisomers assigned the native compound to be SPH m18:1(14Z). This indicates that 1-deoxySLs are metabolized differently than canonical

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“…Fenofibrat jest aktywatorem PPAR-a, przez który reguluje stężenie TG i HDL-C, a jednocześnie wpływa na metabolizm komórek nerwowych i stymuluje produkcję tlenku azotu (NO, nitric oxide) przez indukowanie endotelialnej syntazy. W modelu eksperymentalnym cukrzycy typu 2 u myszy spontanicznie rozwijających cukrzycę (myszy C57BL/KsJ-db/ /db z mutacją genu dla receptora leptyny) wykazano, że fenofibrat chroni przed rozwojem neuropatii [61]. Dodatkowo fenofibrat obniża stężenie toksycznych sfingolipidów (1-deoksy-sfingolipidy) zaangażowanych w patomechanizm neuropatii cukrzycowej, których stężenie wzrasta w zespole metabolicznym i cukrzycy typu 2 [20].…”

Section: Fibraty W Neurologiiunclassified

Dyslipidemia aterogenna w codziennej praktyce — interdyscyplinarny konsensus polskich ekspertów

Luczak¹,

Jasek

Skrabucha

et al. 2017

Folia Cardiologica

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Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?

Cited by 36 publications

References 42 publications

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

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

Elucidating the chemical structure of native 1-deoxysphingosine

Dyslipidemia aterogenna w codziennej praktyce — interdyscyplinarny konsensus polskich ekspertów

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