CONTRASTING IN-VIVO EFFECTS OF MURINE AND HUMAN APOLIPOPROTEIN A-II -ROLE OF MONOMER VERSUS DIMER

The role of apolipoprotein A-II (apoA-II) in high density lipoprotein (HDL) structure and metabolism has been studied previously in transgen ic mice overexpressing either human or murine apoA-II. These studies h ave shown differences between these two groups of transgenic animals i n the levels of very low density, low density, and high density lipopr oteins, in the HDL particle size distribution, and in the relationship between apoA-II levels and lipoprotein levels. To determine whether t hese differences are due to the fact that human apoA-II is dimeric and murine apoA-II monomeric, me have examined the effects of monomeric h uman apoA-II (hA-IImon) in transgenic mice. Site-directed mutagenesis (Cys(6)-->Ser) was used to generate 15 transgenic founder lines of hA- IImon mice, that contained plasma hA-IImon concentrations over a 10-fo ld range (11 mg/dl to 185 mg/dl). The hA-IImon floated in the d less t han or equal to 1.21 g/ml fraction and migrated as an apoA-II monomer by nonreducing SDS-polyacrylamide gel electrophoresis. HDL levels were not correlated with hA-IImon levels (r = 0.26); HDL particle size and size distribution, as well as very low density and low density lipopr otein levels and sizes, were unchanged compared to nontransgenic contr ol mice. These results suggest that differences between mice overexpre ssing human dimeric apoA-II and those overexpressing murine apoA-II ar e the result of sequence differences between these two apoA-II: molecu les and are not solely due to the fact that human apoA-II exists as a dimer.