title: Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?
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.
authors.affiliation: 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.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Renee
authors.initials: R
authors.lastname: Benghozi
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Alecu
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Pharma Research and Early Development, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Niesor
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: 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.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003929:Diabetic Neuropathies / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009525:Niacin / Q000008:administration & dosage; D013107:Sphingolipids / Q000097:blood*; D014280:Triglycerides / Q000097:blood
chemical_list: D013107:Sphingolipids; D014280:Triglycerides; D009525:Niacin; D011345:Fenofibrate
keywords: 1-deoxysphingolipids; Alanine; Diabetic neuropathy; Fenofibrate; MetS; Niacin; Serine; Serine-Palmitoyltransferase; T2DM; sphingolipids