Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC-III transgenic mice.

We previously showed that human apoC-111 expres- sion in transgenic mice causes hypertriglyceridemia due to the accumulation of enlarged very low density lipoprotein (VLDL)-like particles, with increased triglycerides and apoC- 111 and decreased apoE. In vivo turnover studies indicated the metabolic basis was decreased particle fractional catabolic rate. The presence of enlarged triglyceride-rich particles with prolonged residence time in plasma implied defective lipolysis, but in vitro these particles were good substrates for purified lipoprotein lipase (LPL). In the current study we further characterize the metabolic properties of these parti- cles. We show that expression of a mouse apoC-111 transgene can also cause hypertriglyceridemia with a similar accumula- tion of a VLDL-like particle with increased apoC-I11 and de- creased apoE. A vitamin A fat tolerance test was used to show that MoCIIITg and HuCIIITg mice had similarly delayed clearance of triglyceride-rich postprandial particles. Thus, the previously observed hypertriglyceridemia caused by human apoC-111 transgene expression was not due interspecies in- compatibility but a property of apoC-111. In further experi- ments we showed VLDL from apoC-111 transgenic mice inter- acted poorly with fibroblast lipoprotein receptors and this could be corrected by adding exogenous apoE. In addition, control VLDL interaction could be decreased by exogenous apoC-111. Moreover, the hypertriglyceridemia of HuCIIITg mice could be normalized by crossbreeding with HuETg mice. I Thus, a functionally significant reciprocal relationship of apoC-111 and apoE exists, presumably due to competition for space on the surface of triglyceride-rich lipoproteins. Finally, VLDL from HuCIIITg and MoCIIITg mice showed decreased binding to heparin-Sepharose. This suggests an additional locus of the defect in these mice could potentially be in the binding 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-I11 transgenic mice based on the observation of a prolonged residence time of enlarged triglyceride-rich lipoproteins.-AaltoSetda, K., P. H. Wein- stock, C. L. Bisgaier, L. Wu, J. D. Smith, and J. L. Breslow. Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC- 111 transgenic mice.). LipidRes. 1996.37: 1802-1811.