Apolipoprotein A-II/A-I ratio is a key determinant in vivo of HDL concentration and formation of pre-beta HDL containing apolipoprotein A-II

Overexpression of human apolipoprotein A-II (apo A-H) in mice induced postp randial hypertriglyceridemia and marked reduction in plasma HDL concentrati on and particle size [Boisfer et al. (1999) J. Biol. Chem. 274, 11564-11572 ]. We presently compared lipoprotein metabolism in three transgenic lines d isplaying plasma concentrations of human apo A-If ranging from normal to 4 times higher, under ad libitum feeding and after an overnight fast. Fasting dramatically decreased VLDL and lowered circulating human apo A-II in tran sgenic mice; conversely, plasma HDL levels increased in all genotypes. The apo A-I content of HDL was inversely related to the expression of human apo A-II, probably reflecting displacement of apo A-I by an excess of apo A-H. Thus, the molar ratios of apo A-II/A-I in HDL were significantly higher in fed as compared with fasted animals of the same transgenic line, while end ogenous LCAT activity concomitantly decreased. The number and size of HDL p articles decreased in direct proportion to the level of human apo A-II expr ession. Apo A-II was abundantly present in all HDL particles, in contrast t o apo A-I mainly present in large ones. Two novel findings were the presenc e of pre-beta migrating HDL transporting only human apo A-II in the higher- expressing mice and the increase of plasma HDL concentrations by fasting in control and transgenic mice. These findings highlight the reciprocal modif ications of VLDL and HDL induced by the feeding-fasting transition and the key role of the molar ratio of apo A-II/A-I as a determinant of HDL particl e metabolism and pre-beta HDL formation.