Atherosclerosis 219 (2011) 855–863 Contents lists available at SciVerse ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Plasma levels of sphingosine-1-phosphate and apolipoprotein M in patients with monogenic disorders of HDL metabolism Ratna Karuna a,b,c , Rebekka Park b,c,d , Alaa Othman a,b,c , Adriaan G. Holleboom e , Mohammad Mahdi Motazacker e , Iryna Sutter a,b,f , Jan Albert Kuivenhoven e , Lucia Rohrer a,f , Hugues Matile g , Thorsten Hornemann a,f , Markus Stoffel c,d,f , Katharina M. Rentsch a,c,f,1 , Arnold von Eckardstein a,c,f,∗,1 a Institute of Clinical Chemistry, University and University Hospital Zurich, Switzerland b Life Science Zurich PhD Program on Systems Biology of Complex Diseases, ETH Zurich and University of Zurich, Switzerland c Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Switzerland d Institute for Systems Physiology and Metabolic Diseases, ETH Zurich, Switzerland e Department of Experimental Vascular Medicine, Amsterdam Medical Center, The Netherlands f Competence Center for Integrated Human Physiology, University of Zurich, Switzerland g Hoffmann-La Roche Ltd., Pharma Research Basel, Discovery Technology, Basel, Switzerland article info Article history: Received 26 April 2011 Received in revised form 19 August 2011 Accepted 29 August 2011 Available online 6 September 2011 Keywords: HDL apoM Sphingosine-1-phosphate apoA-I ABCA1 LCAT CETP SCARB1 Endothelial lipase Hepatic lipase abstract Background: Apolipoprotein M (apoM) has been identified as a specific sphingosine-1-phosphate (S1P) binding protein of HDL. Objectives and methods: To investigate the in vivo effects of disturbed apoM or HDL metabolism we quantified S1P and apoM in plasmas of wild-type, apoM-knock-out, and apoM transgenic mice as well as 50 patients with seven different monogenic disorders of HDL metabolism and their 51 unaffected relatives. Results: Compared to wild type mice, S1P plasma levels in apoM knock-out and apoM transgenic mice were decreased by 30% and increased by 270%, respectively. Compared to family controls, S1P and apoM levels in apoB-depleted plasma were significantly decreased by in average 34% and 12%, respectively, in heterozygous carriers of mutations in APOA1, LCAT or ABCA1, and by 70% and 48%, respectively, in carriers of two defective alleles in LCAT or ABCA1. Heterozygous mutations in CETP, SCARB1, LIPC, or LIPG did not significantly affect S1P or apoM concentrations. Albumin-corrected molar S1P-to-apoM ratios varied from 0.12 to 0.8 (median 0.3) and were not affected by any mutation. S1P levels in apoB-depleted plasma correlated significantly with HDL-cholesterol and less so with apoM both if apoA-I plasma concentrations were below the median. Conclusion: In the context of previous data, our findings can be explained by the existence of a specific apoM and S1P containing HDL subclass which contains a considerable molar excess of apoM over S1P and is critically determined by apoA-I up to a threshold concentration around the median found in a Caucasian population. © 2011 Elsevier Ireland Ltd. All rights reserved. ∗ Corresponding author at: Institute of Clinical Chemistry, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Tel.: +41 44 255 22 60; fax: +41 44 255 4590. E-mail address: arnold.voneckardstein@usz.ch (A. von Eckardstein). 1 Both act as equal senior authors. 1. Introduction Sphingosine-1-phosphate (S1P) is produced by the degradation of ceramide into sphingosine, which is subsequently phosphory- lated by sphingosine kinase [1]. As the ligand of at least five different G-protein coupled receptors, S1P exerts many biological activi- ties [1]. Erythrocytes are the main source (∼90%) of S1P found in plasma [2,3]. Circulating S1P is transported by high-density lipoproteins (HDL, ∼50–70%), albumin (∼30%), low and very-low density lipoproteins (LDL and VLDL, respectively; together <10%) 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.08.049