LIPOPROTEIN METABOLISM IN TRANSGENIC MICE OVEREXPRESSING APOA-II

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ApoA-I and apoA-II are the two major apolipoproteins associated with plasma HDL. HDL is a heterogenous particle consisting of several subfractions. Two major classes of HDL particles exist including those with only apoA-I (LpA-I) and those containing apoA-I and apoA-II (LpA- I:A-II). LpA-I is more effective than LpA-I:A-II in protecting against atherosclerosis. The function of apoA-II is poorly understood. Transgenic mice overexpressing mouse apoA-I have higher levels of HDL and a reduced susceptibility to aortic fatty streak lesions. In contrast, mice overexpressing mouse apoA-II develop spontaneous early fatty acid streaks compared to control mice even when maintained on a chow diet. In order to gain insight into the function of apoA-II, we performed in vivo 125I-apoA-I and 131I-apoA-II kinetic studies in mice overexpressing mouse apoA-II 2-3 fold and age matched controls. Plasma lipid levels (mg/dl) in the overexpressors were TC=267-335, Tg=70-344, apoA-I=88-112 and apoA-II=22-55 while controls averaged TC=87plus/minus13, Tg=54plus/minus8, apoA-I=88plus/minus12 and apoA-II=13olus/minus0.5. ApoA-I was catabolized slower than apoA-II in control mice with fractional catabolic rates FCR) of 1.14plus/minus .06 d-1 and 1.57plus/minus.12 d-1, respectively. In apoA-II overexpressors, apoA-I and apoA-II were catabolized slower (FCR=.96plus/minus.06 d-1, production rate (PR)=.010mg/dl and FCR=1.25plus/minus.04d-1, PR=.005mg/dl, respectively). With progressive increases in plasma apoA-II levels there was a parallel in plasma triglycerides and IDL sized lipoproteins containing two major lipoproteins particles, LpB and LpA-II:E. The triglyceride-rich lipoproteins had virtually no apoE by FPLC analysis. Our studies indicate that in marked contrast to human studies, apoA-I catabolism is slower than apoA-II in the mouse. Catabolism of apoA-I and apoA-II was slower in the apoA-II overexpressors compared to the controls. The increased HDL levels in the A-II overexpressors is due to both an increased synthesis and decreased catabolism of HDL. With progressive increases in plasma apoA-II levels there was a parallel increase in plasma triglyceride and IDL sized lipoproteins containing two major lipoprotein particles, LpB and LpA-II:E.