High density lipoprotein (HDL) levels are inversely correlated with the incidence of atherosclerotic cardiovascular diseases. HDL may protect against atherosclerosis by promoting transport of excess cholesterol from peripheral tissues to liver, a process termed reverse cholesterol transport (RCT). In addition, HDL protects low density lipoproteins from oxidative damage known to contribute to the onset and progression of atherosclerosisThe major HDL proteins are apolipoprotein (apo)A-I and apoA-II. Some evidence suggests that apoA-I is directly protective against atherosclerosis, but relatively little is known about the role of apoA-II. Contrasting results have been obtained in mice overexpressing human (h) or murine (m) apo A-II.hapoA-II, a homodimeric protein, seems to confer protection with regard to atherogenesis, in contrast, overproduction of mapoA-II (that is monomeric) has been proposed to be atherogenic. To further investigate the role of apoA-II we measured the initials steps of RCT and the paraoxonase activity in both types of mice. To determine if the observed differences were related to the mono or dimeric forms we studied transgenic mice for hapo A-II rendered monomeric by (Cys6->Ser) mutation (hapoA-IImon).mapoA-II mice had cHDL values 84% higher than control mice, their serum or HDL had a capacity to promote cellular cholesterol efflux that was twice the one of controls. LCAT activity measured with exogenous substrate was not different to the activity of control sera (31.8 +/- 1.8 vs 33.8 +/- 2%) but the endogenous esterification capacity was higher (16 +/- 2.5 vs 7.2 +/- 0.2%). hapoA-II mice with normal cHDL and hapoA-IImon with reduced cHDL had lower capacity to efflux cholesterol and to esterify it than control mice.Paroxonase activities for mapoA-II, hapoA-II and hapoA-IImon were respectively 98, 83 and 73% of control mice serum activityOur results are a clear indication that the metabolic differences observed between m and h apoA-II are not related to the mono or dimeric forms, and above all that RCT is a more complex pathway and that increased activity of some steps is not a proof that peripheral cholesterol will be efficiently eliminated.