title: Dose-dependent effects of rosuvastatin on the plasma sphingolipidome and phospholipidome in the metabolic syndrome.
abstract: BACKGROUND
  Statins are effective cholesterol-lowering agents that reduce cardiovascular disease risk but also have pleiotropic effects that may extend to other lipid classes.
  
  
  OBJECTIVE
  The purpose of this article was to investigate, in a post hoc analysis, the dose-dependent effects of rosuvastatin on plasma sphingolipids and phospholipids in men with the metabolic syndrome.
  
  
  METHODS
  Subjects (n = 12) were studied in a randomized, double-blind, triple-crossover trial of a 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week washouts between treatments. Plasma sphingolipid profiling was determined by liquid chromatography electrospray ionization-tandem mass spectrometry.
  
  
  RESULTS
  Rosuvastatin at 10 mg/d (R10) and 40 mg/d (R40) significantly (all P < .001 unless stated otherwise) lowered plasma cholesterol (-34% and -42% [% change with R10 and with R40, respectively]), low-density lipoprotein cholesterol (-49% and -57%) and triglyceride (-24%, P =.03 and -42%) concentrations. Compared with placebo, R10 and R40 significantly decreased the plasma levels of total sphingolipids including those of ceramide (-33% and -37%), sphingomyelin (-27% and -31%), monohexosylceramide (-40% and -47%), dihexosylceramide (-31% and -34%), and trihexosylceramide (-29% and -31%), and GM3 gangliosides (-29% and -26%), lysophosphatidylcholine (-32% and -37%), alkylphosphatidylcholine (-19% and -19%), phosphatidylcholine (-17% and -19%), alkenylphosphatidylcholine (plasmalogen) (-20% and -22%), alkylphosphatidylethanolamine (-20%, P =.008 and -24%, P =.02), alkenylphosphatidylethanolamine (plasmalogen) (-24%, P =.003 and -23%, P =.007), phosphatidylglycerol (-24%, P =.07, -31%, P =.046), and phosphatidylinositol (-34% and -40%). No significant changes were found with phosphatidylethanolamine and phosphatidylserine. Significant dose effects were found with the majority of the plasma sphingolipids, whereas only phosphatidylcholine, lysophosphatidylcholine, alkylphosphatidylcholine, alkenylphosphatidylcholine (plasmalogen), and phosphatidylinositol had significant dose effects. Similar changes were found with plasma sphingolipids when results were normalized to the total phosphatidylcholine concentration.
  
  
  CONCLUSIONS
  Rosuvastatin dose-dependently lowers plasma sphingolipids and phospholipids, independent of low-density lipoprotein lowering, in men with the metabolic syndrome.
authors.affiliation: Metabolic Research Centre (T.W.K.N., E.M.M.O., G.F.W., D.C.C., P.H.R.B.), School of Medicine and Pharmacology, and Faculty of Engineering (P.H.R.B.), Computing and Mathematics, Perth, Western Australia, Australia; and Metabolomics Laboratory (T.W.K.N., J.M.W., P.J.M.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Theodore W K
authors.initials: TW
authors.lastname: Ng
authors.forename: Esther M M
authors.initials: EM
authors.lastname: Ooi
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.forename: Dick C
authors.initials: DC
authors.lastname: Chan
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Weir
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
mesh_terms: D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood*; D008875:Middle Aged; D010743:Phospholipids / Q000097:blood*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013107:Sphingolipids / Q000097:blood*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010743:Phospholipids; D011743:Pyrimidines; D013107:Sphingolipids; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium