Hypertriglyceridemia in Transgenic Mice

We have generated transgenic mice expressing the human apolipoprotein CII (apoCI ) gene under the transcriptional control of the human cytochrome P450 IA1 (CYPIAl) promoter. Human apoCIt transgenic (HuCIITg) mice exhibited significant basal expression of the transgene (plasma apoCIl level = 26.1±4 mg/dl) and showed further induction of transgene expression after treatment with fl-naphthoflavone. Unexpectedly, HuCIITg mice were hypertriglyceridemic and human apoCII levels correlated strongly to triglyceride levels (R = 0.89, P < 0.0001). Triglyceride levels (mg/dl±SEM) were elevated compared to controls in both the fed (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. However, HuCIITg VLDL showed markedly decreased binding to heparin-Sepharose, suggesting that apoCII-rich, apoE-poor lipoprotein may be less accessible to cell surface lipases or receptors within their glycosaminoglycan matrices. HuCIITg mice are a promising model of hypertriglyceridemia that suggests a more complex role for apoCII in the metabolism of plasma triglycerides. (J. Clin. Invest. 1994. 93:1683-1690.)