Alaa Othman1, Renee Benghozi2, Irina Alecu3, Yu Wei4, Eric Niesor5, Arnold von Eckardstein3, Thorsten Hornemann6. 1. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany. 2. F. Hoffmann-La Roche Ltd, Basel, Switzerland. 3. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. 4. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. 5. Pharma Research and Early Development, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 6. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address: thorsten.hornemann@usz.ch.
Abstract
BACKGROUND: The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine-palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L-alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathy HSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy. OBJECTIVE: In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels. METHODS:Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS:Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P < .001) but had no effect on the typical sphingolipids. In contrast, extended-release niacin had no effect on 1-deoxySL levels although both treatments lowered plasma TG levels. CONCLUSIONS: The lowering of plasma 1-deoxySL levels by fenofibrate in dyslipidemic patients might be a novel therapeutic approach in the prevention and treatment of diabetic neuropathy.
RCT Entities:
BACKGROUND: The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine-palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L-alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathyHSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy. OBJECTIVE: In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels. METHODS: Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS:Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P < .001) but had no effect on the typical sphingolipids. In contrast, extended-release niacin had no effect on 1-deoxySL levels although both treatments lowered plasma TG levels. CONCLUSIONS: The lowering of plasma 1-deoxySL levels by fenofibrate in dyslipidemic patients might be a novel therapeutic approach in the prevention and treatment of diabetic neuropathy.
Authors: Regula Steiner; Essa M Saied; Alaa Othman; Christoph Arenz; Alan T Maccarone; Berwyck L J Poad; Stephen J Blanksby; Arnold von Eckardstein; Thorsten Hornemann Journal: J Lipid Res Date: 2016-05-10 Impact factor: 5.922
Authors: Irina Alecu; Alaa Othman; Anke Penno; Essa M Saied; Christoph Arenz; Arnold von Eckardstein; Thorsten Hornemann Journal: J Lipid Res Date: 2016-11-21 Impact factor: 5.922
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