Arginine-directed glycation by methylglyoxal is a factor decreasing HDL plasma concentration and functionality in vivo

s / Atherosclerosis 241 (2015) e32ee71 e33 duodenal intralipid infusion. The lymphatic HDL was isolated; associated lipid, protein and miRNA composition analyzed. Jejunal explants from IR rats were treated with niacin or nicotinamide and mRNA expression was assessed. Results: In IR rats apo-AI lymphatic HDL secretion was reduced ( 47%), but associated TG content enriched (86%), compared to non-IR rats. Niacin was found to stimulate the secretion of lymph HDL (>60%) compared to nontreated IR rats. Niacin treatment normalized the TG content of lymphatic HDL particles. Niacin but not nicotinamide increased Ppara and Cpt1amRNA, and annulled Tnf alpha mRNA in jejunal explants. Top three regulated miR's by niacin in the lymphHDL fractionwere: rno-miR-223-3p, rno-miR-29c-3p and rno-miR93-5p. Analysis of these miR's (IPA software) showed PPAR signalling to be amongst the significantly predicted pathways. Conclusion: IR reduces the secretion of apoAI HDL into mesenteric lymph, whilst niacin may contribute to improving CVD risk by restoring the number and TG enrichment of intestinal apoAI particles. The altered miRNA profile in response to niacin treatment might be involved in exerting hypolipidemic effects of niacin. EAS-0505. ARGININE-DIRECTED GLYCATION BY METHYLGLYOXAL IS A FACTOR DECREASING HDL PLASMA CONCENTRATION AND FUNCTIONALITY IN VIVO N. Rabbani, P.J. Thornalley. Warwick Medical School, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom Aim: The aim of this study was to quantify the modification of HDL by the glucose-derived reactive metabolite, methylglyoxal, in healthy people and patients with type 2 diabetes (T2DM), characterise structural, functional and physiological consequences of the modification and predict their importance for risk of cardiovascular disease. Methods: Major fractions of HDL were isolated from healthy human subjects and patients with T2DM and fractions modified by methylglyoxal and related dicarbonyl metabolites quantified. HDL fractions were glycated bymethylglyoxal tominimum extent in vitro andmolecular, functional and physiological characteristics determined. A one compartment model of HDL plasma clearance was produced including formation and clearance of dicarbonyl modified HDL. Results: HDL modified by methylglyoxal and related dicarbonyl metabolites accountedfor 2.6% HDL and increased to 4.5% in patients with T2DM. Methylglyoxal modification in vitro induced re-structuring of the HDL particles, decreasing stability and plasma half-life in vivo. It occurred at sites of apolipoprotein A-1 linked to membrane fusion, intramolecular bonding and ligand binding. Kinetic modelling of methylglyoxal modification of HDL predicted a negative correlation of plasma HDL-C with methylglyoxal-modified HDL. This was validated clinically. It also predicted dicarbonyl modification produces 2 e 6% decrease in total plasma HDL and 5 -13% decrease in functional HDL clinically. Conclusions: Methylglyoxal modification of apolipoprotein A-1 may accelerate HDL degradation and impairs its functionality in vivo, likely contributing to increased risk of cardiovascular disease. Quantitation of methylglyoxal-modified HDL may improve cardiovascular disease risk models and therapeutics to decrease methylglyoxal may improve preventive treatment of cardiovascular disease. EAS-0555. IMPAIRED INSULIN SIGNALLING LEADS TO DECREASED EXPRESSION OF GPIHBP1 R.P. Surendran , M. Clemente-Postigo , R.S. Kootte , M.M. van Eijk , L. Garrido-Sanchez , F. Cardona , F. Tinahones , M. Nieuwdorp , G. Dallinga-Thie . 1 Experimental Vascular Medicine, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands; Unidad de Gesti on Clinica Endocrinologia y Nutrici on, Instituto de Investigaci on Biom edica de M alaga (IBIMA) Complejo Hospitalario de M alaga, Malaga, Spain; Vascular Medicine, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands; Medical Biochemistry, Academic Medical Center University of Amsterdam, Amsterdam, The