Abstract 5920: Lecithin Cholesterol Acyltransferase Promotes Reverse Cholesterol Transport and Attenuates Atherosclerosis Progression in New Zealand White Rabbits
Background: Low plasma levels of high density lipoprotein cholesterol (HDL-C) are associated with an increased risk of cardiovascular disease (CVD), and there is an unmet need for novel therapies that raise HDL-C. Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that catalyzes cholesterol esterification during HDL formation, a process believed to play a central role for reverse cholesterol transport (RCT). We hypothesize that raising HDL-C by increasing plasma LCAT enzyme activity may represent a novel approach for the treatment of atherosclerosis and CVD.
Methods and Results: We have engineered a recombinant LCAT protein entity, rLCAT, with markedly enhanced enzyme activity and improved stability when compared to wildtype LCAT. A single injection of rLCAT raises HDL-C up to ~4-fold in New Zealand White (NZW) rabbits and generates large HDL particles that are enriched with cholesterylesters (CE) and apolipoprotein A-I. We have used an isotope-dilution technique coupled with GC/MS analysis to assess the flux of labeled cholesterol in rLCAT-treated NZW rabbits. rLCAT-mediated increase of plasma HDL-C was associated with increased cholesterol efflux from peripheral tissues into plasma, a higher plasma cholesterol esterification rate, and an increased rate of neutral sterol excretion in feces, indicating enhanced RCT. To assess the effect of rLCAT on atherosclerosis, we fed NZW rabbits a diet supplemented with 0.2%(w/w) cholesterol for 4 months, followed by treatment with rLCAT for 5 months. Compared to vehicle-treated animals, rLCAT-treated rabbits exhibited a sustained ~3-fold increase of HDL-C, significantly reduced CE accumulation in abdominal aorta plaques and attenuated lesion progression in both abdominal and thoracic aortas. Plasma CE of rLCAT treated rabbits had a higher proportion of linoleate and lower proportion of oleate.
Conclusions: We have generated a novel LCAT protein entity that effectively raises HDL-C and generates large HDL particles in rabbits, promotes RCT and attenuates atherosclerosis. We conclude that recombinant LCAT administration may represent a novel approach for the treatment of atherosclerosis and the dyslipidemia associated with low HDL.