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 expresser line with serum triglycerides of -280 mg/dl, and a high expressor line with serum triglycerides of -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 expresser mice, respectively. Under electron microscopy, VLDL particles from low and high expresser 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 expresser 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 expresser mice and no differences were observed. Also, VLDLs obtained from control and high expresser mice were found to be equally good substrates for purified LPL

When rat hepatocytes were incubated with albumin complexed to the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), rather than to oleic acid (OA), the secretion of newly synthesized apoprotein B100 (apoB100) or B48 (apoB48) was reduced, despite stimulation of cellular triglyceride synthesis by all three fatty acids. When pulse-chase studies of apoB synthesis and secretion were performed in the presence of OA, EPA, or DHA, there were no significant changes in the initial synthetic rates of either apoB species. However, during the chase period, the total recovery of labeled apoB100 and apoB48 from the cell and medium was less in the n-3 fatty acid groups, so that by 150 min, approximately half as much labeled apoB was recovered as in the OA group. Overall, the decreased accumulation in medium of labeled apoB in the presence of EPA and DHA could be quantitatively accounted for by increased degradation of intracellular apoB. Thus, in the primary hepatocyte, apoB degradation is not constitutive, but can be regulated by n-3 fatty acids. (J. Clin. Invest. 1993.