Abstract
Elevated levels of low density lipoprotein (LDL) is a well known independent risk factor for atherosclerotic development. LDL can infiltrate the endothelial cell layer of the artery where it can become stuck to proteoglycans, depositing lipid and initiating atherosclerosis. High density lipoprotein (HDL) removes lipid from the arterial wall via reverse cholesterol transport (RCT) and takes it back to liver for either reutilisation or excretion. Unlike LDL, HDL is anti-atherogenic, and a low level of HDL is associated with development of cardiovascular disease (CVD). However, in subjects with Tangier disease, a condition characterised by a near absence of HDL, subjects do not often develop CVD – which poses a contradictory situation. The aim of the current study was to characterise LDL from Tangier disease subjects, in which we hypothesised it to be less atherogenic than normal LDL.
Tangier LDL was found to have a differential apolipoprotein B-100 (apoB) conformation compared to normal, a characteristic attributable to the altered lipid composition. We also found that Tangier LDL severely lacked a complement of plasma proteins usually found on normal LDL – a characteristic that could make Tangier LDL less atherogenic. Of interest Tangier LDL had approximately one tenth the amount of apolipoprotein E (apoE), a known ligand of the LDL receptor (LDLR). There was a trend that Tangier LDL had a decreased uptake by HepG2 cells compared to normal, a phenomena that could not be changed by increasing the apoE content of Tangier LDL. The altered conformation of apoB therefore remains the key suspect to the observed differential cellular uptake. The uptake assays did not explain the hypothesized lack of atherogenicity in Tangier LDL. We developed a proteoglycan-binding assays but it was largely unsuccessful and needed more optimisation.
The results presented in this report represent a novel analysis of Tangier LDL, a disease that exemplifies a paradox to what is known about the development of heart disease. Current therapies aimed at reducing LDL cholesterol, especially with statins, have proved only partially effective. Further studies of Tangier LDL could be a gateway into exciting new therapies that put more emphasis on altering lipid and/or protein composition.