FURTHER CHARACTERIZATION OF THE METABOLIC PROPERTIES OF TRIGLYCERIDE-RICH LIPOPROTEINS FROM HUMAN AND MOUSE APOC-III TRANSGENIC MICE

We previously showed that human apoC-III expression in transgenic mice causes hypertriglyceridemia due to the accumulation of enlarged very low density lipoprotein (VLDL)-like particles, with increased triglyce rides and apoC-III and decreased apoE. In vivo turnover studies indica ted the metabolic basis was decreased particle fractional catabolic ra te. The presence of enlarged triglyceride-rich particles with prolonge d residence time in plasma implied defective lipolysis, but in vitro t hese particles were good substrates for purified lipoprotein lipase (L PL). In the current study we further characterize the metabolic proper ties of these particles. We show that expression of a mouse apoC-III t ransgene can also cause hypertriglyceridemia with a similar accumulati on of a VLDL-like particle with increased apoC-III and decreased apoE. A vitamin A fat tolerance test was used to show that MoCIIITg and HuC IIITg mice had similarly delayed clearance of triglyceride-rich postpr andial particles. Thus, the previously observed hypertriglyceridemia c aused by human apoC-III transgene expression was not due interspecies incompatibility but a property of apoC-III. In further experiments we showed VLDL from apoC-III transgenic mice interacted poorly with fibro blast lipoprotein receptors and this could be corrected by adding exog enous apoE. In addition, control VLDL interaction could be decreased b y exogenous apoC-III. Moreover, the hypertriglyceridemia of HuCIIITg m ice could be normalized by crossbreeding with HuETg mice. Thus, a func tionally significant reciprocal relationship of apoC-III and apoE exis ts, presumably due to competition for space on the surface of triglyce ride-rich lipoproteins. Finally, VLDL from HuCIIITg and MoCIIITg mice showed decreased binding to heparin-Sepharose. This suggests an additi onal locus of the defect in these mice could potentially be in the bin ding of triglyceride-rich lipoproteins to heparan sulfate proteoglycan matrix on the surface of endothelial cells in which LPL is embedded. This could explain the predicted functional lipase deficiency in apoC- III transgenic mice based on the observation of a prolonged residence time of enlarged triglyceride-rich lipoproteins.