Receptor-Independent Lipid Exchange of ApoA-I Amyloidogenic Variants in Reconstituted High-Density Lipoprotein

• High-density lipoproteins (HDLs) are responsible for removing cholesterol from arterial walls, through a process known as reverse cholesterol transport. The main protein in HDL, apolipoprotein A-I (ApoAI), is essential to this process, and changes in its sequence significantly alter HDL structure and functionality. ApoA-I amyloidogenic variants, associated with a hereditary degenerative disease, are particularly effective at facilitating cholesterol removal, thus protecting carriers from cardiovascular disease. Thus, it is conceivable that reconstituted HDL (rHDL) formulations containing ApoA-I proteins with functional/structural features of amyloidogenic variants hold potential as a promising therapeutic approach. In this work, we explored the effect of protein cargo and lipid composition on the function of rHDL containing either the native ApoA-I or the amyloidogenic variants G26R and L174S. Moreover, we uncovered the structural and functional differences between rHDL particles to comprehend structural features that cause a rise in cholesterol efflux activity despite an apparent lower phospholipid (PL)affinity. Our findings indicate distinct trends in lipid exchange (removal versus deposition) capacities of various rHDL particles depending on protein cargo and PL unsaturation. Notably, the choice of lipid cargo influenced rHDL structure, resulting in smaller and more elliptical particles when POPC was used instead of DMPC. The study highlights the importance of the protein cargo, along with lipid composition, in shaping rHDL structure, contributing to our understanding of lipid-protein interactions and their behaviour.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Nyckelord

High-density lipoprotein

small angle X-ray scattering

reconstitute High-density lipoprotein

neutron reflection

Apolipoprotein A-I.

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)