OVEREXPRESSION OF APOLIPOPROTEIN-CII CAUSES HYPERTRIGLYCERIDEMIA IN TRANSGENIC MICE

We have generated transgenic mice expressing the human apolipoprotein CII (apoCII) gene under the transcriptional control of the human cytoc hrome P-450 IA1 (CYPIA1) promoter. Human apoCII transgenic (HuCIITg) m ice exhibited significant basal expression of the transgene (plasma ap oCII level = 26.1+/-4 mg/dl) and showed further induction of transgene expression after treatment with beta-naphthoflavone. Unexpectedly, Hu CIITg mice were hypertriglyceridemic and human apoCII levels correlate d strongly to triglyceride levels (R = 0.89, P < 0.0001). Triglyceride levels (mg/dl+/-SEM) were elevated compared to controls in both the f ed (804+/-113 vs 146+/-18, P < 0.001) and fasted (273+/-39 vs 61+/-4, P < 0.001) states. HuCIITg mice accumulated triglyceride-rich very low density lipoproteins (VLDL) with an increased apoC/apoE ratio. Tracer kinetic studies indicated delayed clearance of VLDL-triglyceride, and studies using Triton inhibition of VLDL clearance showed no increase in VLDL production. Plasma from these mice activated mouse lipoprotein lipase normally and radiolabeled VLDL were normally hydrolyzed. Howev er, HuCIITg VLDL showed markedly decreased binding to heparin-Sepharos e, suggesting that apoCII-rich, apoE-poor lipoprotein may be less acce ssible to cell surface lipases or receptors within their glycosaminogl ycan matrices. HuCIITg mice are a promising model of hypertriglyceride mia that suggests a more complex role for apoCII in the metabolism of plasma triglycerides.