Human apolipoprotein A-II inhibits the formation of pre-beta high density lipoproteins.
The role of human apolipoprotein A-II (apoA-II) in the remodeling of human high density lipoproteins (HDL) was investigated during incubation of native and reduced-carboxamidomethylated (RCM) HDL3 with a lipoprotein-depleted plasma fraction (LPDP) in the presence of triglyceride-rich particles (TGRP) isolated from Intralipid. Reduction-carboxamidomethylation of HDL3 entirely converts the disulfide-linked apoA-II dimers into monomers, without affecting the structure, composition and particle size distribution of HDL3. Following incubation with LPDP and TGRP, unmodified HDL3 are mainly converted into large, HDL2 particles (diameter: 9.90 +/- 0.07 nm), enriched in triglycerides and depleted of cholesteryl esters. RCM-HDL3 are converted into both large HDL2 (9.86 +/- 0.07 nm) and small (7.53 +/- 0.06 nm) HDL3. The small products are protein-rich and cholesterol-poor, and consist of two different particles: a component with pre-beta mobility, containing only apoA-I, and a component with alpha mobility, containing both apoA-I and apoA-II. Kinetic studies suggest that a two-step process is involved in the formation of small, pre beta-HDL3, by which changes in lipid composition cause alterations in lipoprotein structure/stability, favoring the dissociation of apolipoproteins and reduction of particle size. These findings indicate that apolipoprotein structure is a major determinant of HDL remodeling, apoA-II potentially counteracting the anti-atherogenic properties of apoA-I by inhibiting the formation of small, pre-beta-migrating HDL.
Calabresi
L
L
Center E. Grossi Paoletti, Institute of Pharmacological Sciences, University of Milano, Italy.
Lucchini
A
A
Vecchio
G
G
Sirtori
C R
CR
Franceschini
G
G
D000328:Adult; D016633:Apolipoprotein A-II / Q000494:pharmacology*; D001769:Blood / Q000378:metabolism; D004229:Dithiothreitol / Q000737:chemistry; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D007460:Iodoacetamide / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000737:chemistry / Q000187:drug effects*; D010084:Oxidation-Reduction; D010316:Particle Size; D014280:Triglycerides / Q000378:metabolism
D016633:Apolipoprotein A-II; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D014280:Triglycerides; D004229:Dithiothreitol; D007460:Iodoacetamide