APOLIPOPROTEIN A-II PRODUCTION-RATE IS A MAJOR FACTOR REGULATING THE DISTRIBUTION OF APOLIPOPROTEIN-A-I AMONG HDL SUBCLASSES LPA-I AND LPA-I-A-II IN NORMOLIPIDEMIC HUMANS

HDLs are heterogeneous in their apolipoprotein composition. Apolipopro tein (ape) A-I and apoA-II are the major proteins found in HDL and for m the two major HDL subclasses: those that contain only apoA-I (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I:A-II). Substant ial evidence indicates that these two subclasses differ in their in vi vo metabolism and effect on atherosclerosis, with LpA-I the more speci fically protective subfraction against atherosclerosis. The purpose of this study was to investigate the effect of apoA-I: and apoA-II produ ction and catabolism on plasma LpA-I and LpA-I:A-II levels. Fifty norm olipidemic subjects (those with HDL cholesterol levels in the top and bottom tenth percentiles were excluded) underwent kinetic studies with radiolabeled apoA-I and apoA-II, and the kinetic parameters of apoA-I and apoA-II were correlated with LpA-I and LpA-I:A-II levels. ApoA-I levels were strongly correlated with apoA-I residence times and less s trongly correlated with apoA-I production rates. In contrast, apoA-II levels were correlated only with apoA-II production rates and not with apoA-II residence times. Levels of apoA-I in LpA-I were correlated wi th apoA-I residence times, whereas levels of apoA-I in LpA-I:A-II were correlated primarily with apoA-II production rates. The fraction of a poA-I in LpA-I was highly inversely correlated with apoA-II production rate (r=-.67, P<.001). In multiple regression analysis, apoA-II produ ction rate was the most significant independent variable determining p ercent apoA-I in LpA-I among all the kinetic parameters. These results indicate that in normolipidemic individuals (1) apoA-I levels are reg ulated primarily by apoA-I catabolism and apoA-II levels by apoA-II pr oduction; (2) the rate of catabolism of apoA-I is an important factor determining LpA-I levels, while the rate of apoA-II production is the major determinant of the amount of apoA-I in LpA-I:A-II; and (3) the r ate of apoA-II production is a major factor determining the distributi on of apoA-I between LpA-I and LpA-I:A-II, thereby possibly modulating susceptibility to atherosclerosis in humans.