Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated
triglyceride levels. In this report, the mechanism for the
hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum
triglycerides of approximately 280 mg/dl, and a high expressor line with serum
triglycerides of approximately 1,000 mg/dl. Elevated
triglycerides were mainly in VLDL. VLDL particles were 1.5 times more
triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse
apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue
lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in
hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by
lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased
VLDL triglyceride, but not
apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in
triglyceride, but not
apo B or total
protein, secretion in high expressor mice compared with controls. In summary,
hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of
triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased
apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary
familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common
lipoprotein disorder.