| Low plasma concentrations of high density lipoprotein cholesterol (HDL-c) and apolipoprotein A-I (apoA-I) have been recognized as independent risk factors for atherosclerotic cardiovascular disease. Although the most frequent metabolic abnormality associated with low HDL is hypertriglyceridemia, the mechanisms responsible for HDL lowering in hypertriglyceridemic states have not been fully elucidated. Therefore, we investigated the roles of the following processes on HDL metabolism: triglyceride (TG) enrichment of HDL, a process that occurs as a consequence of hypertriglyceridemia, and lipolytic modification of HDL by the lipoprotein enzyme hepatic lipase (HL). In the New Zealand white (NZW) rabbit, an animal model naturally deficient in HL, we compared the rate of clearance of rabbit HDL that had been TG enriched (by incubation with human very low density lipoprotein) to native rabbit HDL that was relatively TG-poor, both in the absence and presence of HL. Results of our kinetic experiments demonstrated that, in the absence of HL, apoA-I and cholesteryl ester (CE) associated with TG-rich and TG-poor HDL are cleared at the same rate (P = 0.68 and P = 0.20, respectively; n = 9 animals in each group). In contrast, apoA-I associated with TG-rich HDL that had been lipolyzed ex vivo by catalytically-active HL was cleared 22% more rapidly than TG-rich HDL incubated with heat-inactivated HL, and 26% more rapidly than TG-poor HDL incubated with active HL (P < 0.05 for both, n = 18 animals total). Furthermore, rabbits expressing human HL (as a result of adenovirus-mediated transfer of the human HL transgene) showed a 50% enhancement (P < 0.01) in the clearance of TG-rich versus TG-poor HDL apoA-I, whereas there was no difference in the clearance of the HDL tracers in lacZ control rabbits (n = 6 animals in each group). It is concluded that TG enrichment of HDL with subsequent lipolysis by HL, either ex vivo or in vivo, enhances HDL apoA-I clearance. Conversely, neither TG enrichment of HDL without HL-mediated lipolysis, nor HL-mediated lipolysis in the absence of prior TG-enrichment of HDL, is sufficient to enhance HDL clearance. These data provide further support for the important interaction between HDL TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states. |
