Plasma levels of sphingosine-1-phosphate and apolipoprotein M in patients with monogenic disorders of HDL metabolism

Background: Apolipoprotein M (apoM) has been identified as a specific sphingosine-1-phosphate (SIP) binding protein of HDL. Objectives and methods: To investigate the in vivo effects of disturbed apoM or HDL metabolism we quantified SIP 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, SIP plasma levels in apoM knock-out and apoM transgenic mice were decreased by 30% and increased by 270%, respectively. Compared to family controls, SIP 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 SIP or apoM concentrations. Albumin-corrected molar SIP-to-apoM ratios varied from 0.12 to 0.8 (median 0.3) and were not affected by any mutation. SIP 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 SIP containing HDL subclass which contains a considerable molar excess of apoM over SIP and is critically determined by apoA-I up to a threshold concentration around the median found in a Caucasian population. (C) 2011 Elsevier Ireland Ltd. All rights reserved.