Effects of Particle Size and Protein Composition on Structural Stability and Functional Remodeling of Human High‐Density Lipoproteins

High‐density lipoproteins (HDL) are protein‐lipid complexes that prevent atherosclerosis by removing cell cholesterol. During cholesterol transport, HDL undergo fusion and rupture upon remodeling by plasma factors, and form subclasses differing in size, composition and function. Thus, large HDL are more cardioprotective than small HDL, while HDL(A‐I/A‐II) containing proteins A‐I and A‐II are thought to be less cardioprotective than HDL(A‐I) containing only A‐I, since A‐II is thought to inhibit HDL remodeling. To provide the basis for these functional differences, we tested the effects of particle size and composition on HDL stability, fusion and rupture. Our spectroscopic, light scattering, calorimetric, electron microscopic, and biochemical studies show that HDL stability decreases with increasing particle size. This may enhance cholesterol uptake from large lipid‐loaded HDL. Surprisingly, HDL(A‐I/A‐II) are slightly less stable than HDL(A‐I). Thus, contrary to the existing notion, A‐II promotes HDL fusion and A‐I dissociation; interestingly, A‐II inhibits HDL rupture. This effect, which may be due to deep penetration of the hydrophobic A‐II into the lipid, may shift the population towards larger more cardioprotective HDL. These results shed new light on the role of particle size and protein composition in HDL remodeling, and help reconcile conflicting reports regarding the role of A‐II on HDL. NIH grants: GM067260 and HL026355