Apolipoprotein A-I charge and conformation regulate the clearance of reconstituted high density lipoprotein in vivo

While low apolipoprotein A-I (apoA-I) levels are primarily associated with increased high density lipoprotein (HDL) fractional catabolic rate (FCR), t he factors that regulate the clearance of HDL from the plasma are unclear. In this study, the effect of lipid composition of reconstituted HDL particl es (LpA-I) on their rate of clearance from rabbit plasma has been investiga ted. Sonicated LpA-I containing 1 to 2 molecules of purified human apoA-I a nd 5 to 120 molecules of palmitoyl-oleoyl phosphatidylcholine (POPC) exhibi t similar charge and plasma FCR to that for lipid free apoA-I, 2.8 pools/da y. Inclusion of 1 molecule of apoA-II to an LpA-I complex increases the FCR to 3.5 pools/day, a value similar to that observed for exchanged-labeled H DL3. In contrast, addition of 40 molecules of triglyceride, diglyceride, or cholesteryl ester to a sonicated LpA-I containing 120 moles of POPC and 2 molecules of apoA-I increases the negative charge of the particle and reduc es the FCR to 1.8 pools/day. Discoidal LpA-I are the most positively charge d lipoprotein particles and also have the fastest clearance rates, 4.5 pool s/day, Immunochemical characterization of the different LpA-I particles sho ws that the exposure of an epitope at residues 98 to 121 of the apoA-I mole cule is associated with an increased negative particle charge and a slower clearance from the plasma.jlr We conclude that the charge and conformation of apoA-I are sensitive to the lipid composition of LpA-I and play a centra l role in regulating the clearance of these lipoproteins from plasma.