Abstract
Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects.
Highlights
Need to characterize lipoprotein particles using a range of additional parameters such as size, particle number and chemical composition[13], which is expected to improve the assessment of cardiovascular disease (CVD) risk and guide lipid-lowering therapies[14]
The structure of lipoproteins has been inferred to date from compositional analyses using the classical theoretical description of Shen and colleagues[15], by which the structure of circulating lipoproteins is consistent with a spherical model of radius r in which a spherical liquid core of cholesterol esters and triglycerides is surrounded by a monolayer of free cholesterol and phospholipids, with proteins closely packed with the hydrophilic head groups of phospholipids on the outer surface of the particle
On the basis of an updated version of the spherical model proposed by Shen et al and experimental data on HDL by 1H-NMR spectroscopy, the theoretical size of HDL particles has been estimated and a positive correlation found with the high-density lipoprotein cholesterol (HDL-C)/ApoA-I ratio[16]
Summary
Need to characterize lipoprotein particles using a range of additional parameters such as size, particle number and chemical composition[13], which is expected to improve the assessment of CVD risk and guide lipid-lowering therapies[14]. On the basis of an updated version of the spherical model proposed by Shen et al and experimental data on HDL by 1H-NMR spectroscopy, the theoretical size of HDL particles has been estimated and a positive correlation found with the HDL-C/ApoA-I ratio[16] In this regard, the emergence of experimental techniques mainly based on NMR spectroscopy makes it possible to characterize the size and particle number of lipoprotein particles[16,17]. Our study aims to gain greater insight into how some of the aforementioned HDL parameters are related (for example, the mean HDL size and the HDL subclass distribution), and how these parameters are affected by the lipid and protein concentrations in the healthy and the DM2 pathological state with atherogenic dyslipidemia For this purpose, we used classical biochemical enzymatic techniques and advanced 1H-NMR spectroscopy, atomic force microscopy (AFM) and fluorescence experiments to model the HDL structure and to characterize the size, and the molecular composition and distribution of the HDL fraction. We performed the same analysis on the DM2 group after two pharmacological interventions with fenofibrate and niacin, respectively
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