Overexpression of human apolipoprotein A-II in mice induces hypertriglyceridemia due to defective very low density lipoprotein hydrolysis

Two lines of transgenic mice, hAIItg-delta and hAIItg-lambda, expressing hu man apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, res pectively, displayed on standard chow postprandial chylomicronemia, large q uantities of very low density lipoprotein (VLDL) and low density lipoprotei n (LDL) but greatly reduced high density lipoprotein (HDL), Hypertriglyceri demia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and cont rol mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activitie s decreased at most by 30% in transgenic mice, whereas adipose tissue and m uscle LPL activities were unaffected, indicating normal LPL synthesis. Howe ver, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent V-max of the re action decreasing proportionately to human apoA-II expression. Human apoA-I I was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasm a from control mice induced a dose-dependent decrease in LPL and hepatic li pase activities. In conclusion, overexpression of human apoA-II in transgen ic mice induced the proatherogenic lipoprotein profile of low plasma HDL an d postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL.