Expression of Human Hepatic Lipase in the Rabbit Model Preferentially Enhances the Clearance of Triglyceride-Enriched Versus Native High-Density Lipoprotein Apolipoprotein A-I

Abstract

Background— We have shown previously that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, contributes to HDL lowering in humans by enhancing the clearance of HDL apolipoprotein (apo) A-I from the circulation. In the New Zealand White rabbit, an animal naturally deficient in hepatic lipase (HL), we demonstrated that TG enrichment of HDL per se is not sufficient to enhance HDL clearance in the absence of ex vivo lipolysis by HL. Here, we examined in the rabbit the interaction between in vivo HL lipolytic action and HDL TG enrichment on the subsequent metabolic clearance of HDL apoA-I. Methods and Results— The clearance of HDL, TG-enriched with human VLDL (12% mass TG), was compared with a simultaneously injected native rabbit HDL tracer (8% TG) 5 to 7 days after injection of recombinant (r) adenovirus expressing either the human HL or lacZ transgene (n=6 animals each). In rHL-Adv rabbits, HL activity levels were 2- to 7-fold higher (versus rlacZ-Adv controls; P <0.01), and there were significant ( P <0.05) reductions in HDL TG (−18%), cholesterol (−21%), cholesteryl ester (−24%), and phospholipid (−14%). Moreover, the clearance of TG-enriched versus native HDL was significantly greater (by 50%; 0.122±0.022 versus 0.081±0.015 pools/h; P <0.01) in rHL-Adv rabbits but not in controls. Conclusions— These studies have shown that TG enrichment of HDL in the presence but not in the absence of in vivo expression of moderate levels of lipolytically active HL results in enhanced HDL clearance, demonstrating the important interaction between TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.