We all have heard about the good and bad cholesterol and how these are affected by diet. Good cholesterol or high density lipoprotein (HDL) removes lipids from the vessels to get excreted in the liver. Bad cholesterol or low density lipoprotein (LDL) deliver lipids to the body. The truth is that both good and bad cholesterol are needed in lipid metabolism and there is an equilibria between the number of these particles in the body that is critical to maintain a healthy life. However, some times both LDL and HDL change and these changes lead to the onset of atherosclerosis, the main killer of the west. Due to the large complexity in composition (and structure) as well as the experimental complexity in clinical and animal studies, it becomes difficult to pinpoint what is exactly in lipoproteins that causes the onset of atherosclerosis. We know already that oxidation and glycosylation is important, and that the presence of specific apolipoprotein variants also are thought of clinical markers for this disease. Simplified models that mirror the functional behavior of lipoproteins are thus urgently needed.
By using deuteration of both lipids and sterols, we formed model, fluid membranes with various compositions: saturated versus unsaturated lipids in the presence and absence of cholesterol. These membranes were then exposed to lipoproteins extracted from human blood serum and the lipid exchange that takes between the lipoprotein and the model membrane was then followed by neutron reflection. This technique then enables distinguishing the fraction of lipids that are deposited (hydrogenated) from the lipid fraction that is removed (deuterated) and replaced by solvent. Our recent publication at BBA – Molecular and Cell Biology of Lipids demonstrates that, despite the simplicity of the model system, the exchange data mirror key clinical findings since: 1) HDL was found to remove lipids to a larger extent than LDL, 2) saturated fats were cleared to a larger extent by HDL than by LDL, while the presence of cholesterol in the membrane significantly reduced the ability of lipoproteins to exchange lipids, 3) lipoproteins present low affinity for unsaturated phospholipids which explains why HDL therapy is able to re-model plaque composition, and 4) denser LDL (with higher protein content) deposit more lipids on model membranes in agreement with the atherogenic characteristics of smaller and denser LDL sub-fractions.
Figure 1. The exchange of lipids between lipoproteins and solid supported lipid bilayers can be followed by NR. Here the effect the composition of the solid supported membrane on the capacity for lipoproteins to exchange fats was determined. In particular, major differences were found between saturated (dDMPC) and unsaturated (dPC) fats and also due to the presence of cholesterol (not shown).
The methodology is now ready to explore lipoproteins extracted from individuals with distinctive serum lipid profiles such as to differentiate between normal levels and high levels of cholesterol and triglyceride, for example. We can also investigate suspected atherogenic subfractions such as the small dense LDL and lipoprotein(a), or the presence of atherogenic apolipoprotein variants such as apoE4. These studies will clarify the role of these fractions and aid unravel the mechanism by which these become atherogenic.
University, the Life Sciences Group at the ILL, the deuteration group at ANSTO, the Institute of Molecular Biotechnology at Graz University of Technology, the clinical research center of Lund University and the Department of Pharmacy at University of Copenhagen. This project is funded by the Swedish Research Council and a PhD studentship of the Institute Laue Langevin. Experiments were performed at ILL and the ISIS neutron and muon source.
Reference to this paper https://www.sciencedirect.com/science/article/pii/S138819812030161X?via%3Dihub