Apolipoprotein A-I-containing particles and reverse cholesterol transport: Evidence for connection between cholesterol efflux and atherosclerosis risk

Abstract

It is now clearly established that apo A-I-containing lipoproteins exist as two major families, those containing apo A-I and apo A-II (LpA-I:A-II) and those containing apo A-I but free of apo A-II (LpA-I). Metabolic studies utilizing radiolabeled lipoprotein particles suggested that there is a kinetic difference between LpA-I and LpA-I:A-II family and support the concept that there may be important functional differences between the lipoprotein particles present within HDL. Of considerable significance was the finding that proteins stimulating reverse cholesterol transport (lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP)) are mainly present in LpA-I and not in LpA-I:A-II family. Cholesterol efflux mediated by A-I-containing particles has been studied in different cells. Long term exposure to LpA-I family promoted cholesterol efflux whereas less efflux was observed in the presence of LpA-I:A-II family. The fact that LpA-I:A-II family can inhibit the LpA-I promoted cholesterol efflux strongly supports the role of apo A-II as an antagonist in the production of cholesterol efflux. These results which emphasize that LpA-I and LpA-I:A-II families behave as distinct entities have been confirmed in other studies showing that they have different clinical significance. The results in mice transgenic for apo A-I indicate that overexpression of apo A-I induces more cholesterol efflux and protects C57BL/6 mice from atherosclerosis. Increased expression of apo A-II in mice appears to decrease cholesterol efflux and to promote rather than retard aortic fatty streak development. Using natural variants of human apo A-I and an immunochemical approach with mapped monoclonal antibodies, we suggest that the region around residue 165 is involved in the interaction of apo A-I with cells. The use of a synthetic tetrameric peptide that mimics properties of apo A-I allowed us to confirm the importance of this particular region in the biological role of apo A-I.