HYPERALPHALIPOPROTEINEMIA IN HUMAN LECITHIN-CHOLESTEROL ACYLTRANSFERASE TRANSGENIC RABBITS - IN-VIVO APOLIPOPROTEIN-A-I CATABOLISM IS DELAYED IN A GENE DOSE-DEPENDENT MANNER

Lecithin cholesterol acyltransferase (LCAT) is an enzyme involved in t he intravascular metabolism of high density lipoproteins (HDLs). Overe xpression of human LCAT (hLCAT) in transgenic rabbits leads to gene do se-dependent increases of total and HDL cholesterol concentrations. To elucidate the mechanisms responsible for this effect, I-131-HDL apoA- I kinetics were assessed in age- and sex-matched groups of rabbits (n = 3 each) with high, low, or no hLCAT expression. Mean total and HDL c holesterol concentrations (mg/dl), respectively, were 162 +/- 18 and 1 21 +/- 12 for high expressors (HE), 55 +/- 6 and 55 +/- 10 for low exp ressors (LE), and 29 +/- 2 and 28 +/- 4 for controls. Fast protein liq uid chromatography analysis of plasma revealed that the HDL of both HE and LE were cholesteryl ester and phospholipid enriched, as compared with controls, with the greatest differences noted between HE and cont rols. These compositional changes resulted in an incremental shift in apparent HDL particle size which correlated directly with the level of hLCAT expression, such that HE had the largest HDL particles and cont rols the smallest. In vivo kinetic experiments demonstrated that the f ractional catabolic rate (FCR, d(-1)) of apoA-I was slowest in HE (0.3 28 +/-0.03) followed by LE (0.408 +/- 0.01) and, lastly, by controls ( 0.528 +/- 0.04). ApoA-I FCR was inversely associated with HDL choleste rol level (r = -0.851, P < 0.01) and hLCAT activity (r = -0.816, P < 0 .01). These data indicate that fractional catabolic rate is the predom inant mechanism by which hLCAT overexpression differentially modulates HDL concentrations in this animal model. We hypothesize that LCAT-ind uced changes in HDL composition and size ultimately reduce apoA-I cata bolism by altering apoA-I conformation and/or HDL particle regeneratio n.