LIPOPROTEIN METABOLISM IN TRANSGENIC MICE OVEREXPRESSING APOA-II

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ApoA-II and apoE are two important apolipoproteins associated with plasma HDL. Transgenic mice overexpressing apoA-II have an increased risk of atherosclerosis and are characterized by elevated plasma triglycerides, HDL and the development of a unique apoE rich lipoprotein (LpE) in the size range of the HDL1 particle. Mice overexpressing mouse apoA-II develop spontaneous early fatty acid streaks compared to control mice even when maintained on a chow diet. Plasma levels of apoA-II (152- 312 mg/dl) and apoE (6-10 mg/dl) were increased when compared to control mice levels of 34 +/- 16 mg/dl and 6.8 +/- 0.7 mg/dl, respectively. To gain insight into the formation of the apoA-II containing HDL and LpE we performed in vivo kinetic studies of 125I-apoE and 131I-apoA-II in A-II transgenic mice (n=8) and age matched controls (n=8). Plasma lipid levels (mg/dl) in A-II transgenic were TC=291-454 mg/dl, Tg=83-279 mg/dl and in control mice TC=128 +/- 29 mg/dl, Tg=84 +/- 38 mg/dl. The catabolism of apoE in A-II transgenic mice was markedly delayed when compared to normals with fractional catabolic rates (FCR) of 6.98 +/- 2.18 d -1 and 12.11 +/- 1.32 d -1, respectively. ApoA-II in A-II transgenic mice was also catabolized slower than normals with FCR=1.15 +/- 0.13d -1, production rate (PR)=19.91 +/- 1.89 mg/g-d and FCR=1.85 +/- 0.17d -1, PR=5.48 +/- 2.16 mg/g-d, respectively. ApoE and apoA-II are catabolized 9 fold and 8 fold faster in mice than humans. On FPLC analysis apoE in control mice was present predominantly on HDL while in A-II transgenic mice the majority of apoE was on the unique apoE rich lipoprotein, LpE in HDL1. Our studies in A-II transgenic mice indicate that apoE is catabolized 2 fold slower than in control mice. The elevated HDL level in A-II transgenic mice is due to a combination of increased synthesis and delayed catabolism of apoA-II. The elevated plasma level of the LpE particle is due predominantly to decreased catabolism of apoE. The LpE particle may play a role in the increased risk of atherosclerosis in A- II transgenic mice.