Tuesday, 26 May 2015

13:45-17:00

http://www.isa-2015.com/

Abstract titleThe effects of a novel apoA-I transcriptional regulator (RVX-208) on whole plasma and HDL lipidomes

AuthorSiebel, Andrew, Baker IDI Heart & Diabetes Institute, Melbourne, Australia (Presenting author)

Co-author(s)Trinh, Si Khiang

Khan, Anmar

Johansson, Jan

Allan, Gordon

Wong, Norman

Otvos, Jim

Rye, Kerry-Anne

Phillip, Barter

Meikle, Peter

Kingwell, Bronwyn

TopicDyslipidemia; Lipids, Lipoproteins and Apolipoproteins

KeywordsApolipoproteins, Diabetes, HDL, Lipids

Abstract text

High-density lipoprotein (HDL) displays altered lipid composition and becomes dysfunctional under conditions of metabolic disease. This study aimed to determine the effects of a novel, first-in-class BET inhibitor with apolipoprotein A-I (apoA-I) inducing effects, RVX-208 on whole plasma and HDL lipidomes.

Twenty unmedicated males (38-69 years) with prediabetes received 100mg b.i.d RVX-208 and placebo each for 29-33 days separated by a wash-out period of 21-35 days in a randomised, cross-over design. Lipoprotein particle concentration was measured by nuclear magnetic resonance (NMR) analysis (LipoScience). Whole plasma and HDL lipid profiles (24 lipid classes containing 342 individual lipid species) were measured in fasting blood samples from 18 out of the 20 participants collected before and after both treatment periods using electrospray-ionisation tandem mass spectrometry.

RVX-208 treatment elicited no significant changes in apoA-I and HDL-C or other conventional lipid measures. The concentration of medium HDL particles increased (p=0.01) and small HDL particles decreased (p=0.04) after RVX-208 treatment. There was no effect of RVX-208 on whole plasma lipid classes or individual lipid species. However, RVX-208 treatment increased the concentration of 8 lipid classes in the HDL lipidome, including ceramides (Cer: RVX-208 vs placebo 21±29%; mean % of change±SD), monohexosylceramides (MHC: 18±23%), trihexosylceramides (THC: 21±30%), GM3 gangliosides (GM3: 23±23%), alkylphosphatidylcholines (PC(O): 19±25%), alkenylphosphatidylcholines (PC(P): 18±24%), lysophosphatidylcholines (LPC: 16±22%) and lysophosphatidylethanolamines (LPE: 23±34%) (all p<0.05; repeated Measures ANOVA with Benjamini-Hochberg correction for multiple comparisons).

In metabolic syndrome, total PC(P) with potential anti-oxidative properties and THC in the HDL lipidome are lower compared to healthy controls (Khan & Meikle, unpublished data). In our population with prediabetes, RVX-208 treatment increased these surface sphingolipid and phospholipid classes towards concentrations observed in healthy controls. Four weeks of treatment with RVX-208 in individuals with prediabetes induces changes in the HDL lipidome without changing the plasma concentrations of either HDL cholesterol or apoA-I.

This study was supported by the National Health & Medical Research Council of Australia (APP1065462), Resverlogix Corp. and in part by the Victorian Government’s Operational Infrastructure Support (OIS) Program.