Defining the Quality of "Good Cholesterol"

Lau, Sophie (2023) Defining the Quality of "Good Cholesterol". In: RSC Faraday Joint Interest Group Conference 2023, 2023-04-03 - 2023-04-05, Sheffield University. (Unpublished)

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Abstract

Reverse cholesterol transport (RCT) from arterial plaques is mediated by high-density lipoprotein cholesterol (HDL-C) nanoparticles, known as “good cholesterol”. Recently, the functional quality of HDL-C has been used as a reliable predictor of cardiovascular health. However, there is a poor understanding of the factors that define the functional quality of HDL-C. The molecular organisation of the lipid and cholesterol could affect the functional interactions of the HDL-C with RCT enzymes and cell receptors. Furthermore, the structure and sequence of the major lipid-bound HDL-C protein, apolipoprotein A-I (apoA-I), are thought to be key targets for understanding the HDL-C functional quality. To define the quality of rHDL-C nanoparticles we are identifying the molecular features of rHDL-C containing functional and dysfunctional apoA-I mutants. We have developed a sensitive tool to detect the particle morphology of oriented rHDL-C using 31P solid-state NMR (ssNMR) spectroscopy. Wherein, the observed NMR lineshape(s) are highly sensitive to the surface curvature of the lipid headgroups.1 We have investigated the orientational distribution of cholesterol in the confined lipid bilayer of discoidal rHDL-C nanoparticles compared to unconstrained lipid bilayers in multilamellar vesicles (MLVs).2 The average orientation and orientational distribution of [2,3,4-13C3]cholesterol in rHDL-C and MLVs was determined using ssNMR measurements of the dynamically-averaged 13C-13C and 13C-1H dipolar couplings. In both lipid environments, only subtle differences were observed in the average cholesterol orientation. Interestingly, cholesterol samples a much greater range of orientations in rHDL-C than in MLVs, in excellent agreement with previous molecular dynamics simulations. The greater orientational disorder of cholesterol in rHDL-C nanoparticles could reflect the plasticity of the particles required for the cellular cholesterol efflux and uptake. A direct functional comparison of the rHDL-C nanoparticles using in vitro cellular assays will measure the cholesterol efflux, hepatic uptake, and cholesterol esterification. Overall, this will inform the development of HDL-C modifying therapies for atherosclerosis, our understanding of HDL interactions in RCT, or aid in the development of predictive tools for cardiovascular disease. 1. S. Lau and D. A. Middleton, Angewandte Chemie (International ed.), 2020, 59, 18126-18130. 2. S. Lau and D. A. Middleton, Physical Chemistry Chemical Physics, 2022, DOI: 10.1039/D2CP02393H.