The anti-atherogenic effect of apolipoprotein A-I (apoA-I) is mainly attributed to its involvement in reverse cholesterol transport, a process where apoA-I accepts cholesterol and phospholipids from peripheral tissues to form high-density lipoprotein (HDL) 1. The conformational flexibility of apoA-I not only allows it to adapt to various lipid contents in HDL, but also contributes to its amyloidogenic propensity in diseases like atherosclerosis and hereditary amyloidosis 2. As HDLs are heterogeneous molecules with various sizes, lipid composition and function, understanding how different lipid contents affect the conformation of apoA-I will provide insights into how the lipid-protein complex performs its function, and how the structure of apoA-I may be destabilised leading to amyloid fibril formation.
The interaction between micellar lipid complexes and apoA-I has been studied extensively before, though the conformation of apoA-I bound to few lipid molecules is less understood. Interestingly, the plasma level of preβ1-HDL, a lipid-poor form of apoA-I, was found to be elevated in coronary artery disease 3. Herein, we used apoA-I interacting with either submicellar lipids or detergents as an experimental model to study the structural features of lipid-poor apoA-I. Detailed characterisation revealed that submicellar lipids and detergents induced differential changes in the thermodynamic stability and hydrophobic surface exposure of apoA-I. Moreover, a vast majority of lipids/detergents stabilised a smaller, more compact form of apoA-I, which was distinct from either the lipid-free or fully lipidated form. Surprisingly, fibril formation was absent when methionine-oxidised apoA-I, which is fibrillogenic, was incubated with submicellar lipids/detergents, even though some lipids/detergents were found to reduce the thermostability of apoA-I. These findings provide new insights into the nature of apoA-I-lipid interaction and prompt further investigations. Future studies should aim to elucidate the molecular details and functional implications of the apoA-I conformation induced by submicellar lipids, and how this interaction prevents amyloid formation.