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

Abstract

While low apolipoprotein A-I (apoA-I) levels are primarily associated with increased high density lipoprotein (HDL) fractional catabolic rate (FCR), the factors that regulate the clearance of HDL from the plasma are unclear. In this study, the effect of lipid composition of reconstituted HDL particles (LpA-I) on their rate of clearance from rabbit plasma has been investigated. Sonicated LpA-I containing 1 to 2 molecules of purified human apoA-I and 5 to 120 molecules of palmitoyl-oleoyl phosphatidylcholine (POPC) exhibit similar charge and plasma FCR to that for lipid free apoA-I, 2.8 pools/day. 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 HDL 3 . 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 reduces the FCR to 1.8 pools/day. Discoidal LpA-I are the most positively charged lipoprotein particles and also have the fastest clearance rates, 4.5 pools/day. Immunochemical characterization of the different LpA-I particles shows that the exposure of an epitope at residues 98 to 121 of the apoA-I molecule is associated with an increased negative particle charge and a slower clearance from the plasma. We conclude that the charge and conformation of apoA-I are sensitive to the lipid composition of LpA-I and play a central role in regulating the clearance of these lipoproteins from plasma. -Braschi, S., T. A-M. Neville, M-C. Vohl, and D. L. Sparks. Apolipoprotein A-I charge and conformation regulate the clearance of reconstituted high density lipoprotein in vivo.

HDL: The Metabolism, Function, and Therapeutic Importance

“…The size and charge of HDL particles restrict their passage through the glomerulus. apoA-I has a much smaller size and therefore can be absorbed in the PCT . These data suggest that cubulin plays a role in the renal clearance of apoA-I and HDL uptake.…”

“…apoA-I has a much smaller size and therefore can be absorbed in the PCT. 188 These data suggest that cubulin plays a role in the renal clearance of apoA-I and HDL uptake.…”

Phosphatidylinositol promotes cholesterol transport in vivo

“…All lipoprotein classes exhibit a net negative charge and studies have shown that this charge is due to both the apolipoprotein composition of the lipoprotein and its content of anionic lipids (specifically phosphatidylinositol (PI)) (21,22). Experiments in this laboratory have shown that interfacially active enzymes are affected by lipoprotein charge and that HDL metabolism in vivo is directly affected by the charge on HDL particles (23). The data suggest that lipoprotein charge may affect cholesterol metabolism in vivo.…”

Probing the Lipid-Free Structure and Stability of Apolipoprotein A-I by Mutation

“…Others, such as cubilin-mediated clearance () or promotion of cholesterol efflux from cells ( , ), may be performed by either lipid-free or lipid-bound apoA-I. The conformation of apoA-I has been shown to play a central role in regulating the functions of this protein ( − ). Therefore, a detailed understanding of the conformation and stability of apoA-I, in both the lipid-free and lipid-bound states, is necessary for a full understanding of its functions.…”