Increased cholesterol efflux potential of sera from ApoA-I-Milano carriersand transgenic mice

The ability of HDL to remove cholesterol from peripheral cells and drive it to the liver for excretion is believed to explain most of the strong inver se correlation between plasma HDL cholesterol levels and coronary heart dis ease. Carriers of the ApoA-I-Milano (A-I-M) mutant have a severe hypoalphal ipoproteinemia but are not at increased risk for premature of coronary hear t disease. To explain this apparent paradox, we compared the capacity of se rum from A-I-M and control subjects to extract cholesterol from Fu5AH cells . Because the A-I-M carriers are all heterozygotes for the mutation, we als o compared the cholesterol efflux capacity of serum from transgenic mice ex pressing A-I-M or wild-type ApoA-I (A-I-WT), in the absence of murine ApoA- I. In the whole series of human or mouse sera, cholesterol efflux was signi ficantly correlated with several HDL-related parameters; after adjustment f or concomitant variables, the only parameter that remained significantly co rrelated with cholesterol efflux was the serum ApoA-I concentration (r(2)=0 .85 in humans and 0.84 in mice). The same was true when samples from contro l subjects, A-I-M carriers, A-I-WT or A-I-M mice were analyzed separately. Cholesterol efflux to sera from the A-I-M carriers was only reduced slightl y compared with control sera (25.0+/-4.2% versus 30.4+/-3.3%), although the re was a large reduction (-45%) in the serum ApoA-I concentration in the fo rmer. Cholesterol efflux was also lower to sera from A-I-M than A-I-WT mice (15.6+/-3.8% versus 30.1+/-7.1%), but less than expected from the 70% redu ction in serum ApoA-I concentration. A relative efflux potential of serum w as calculated in each group as the slope of the regression line fitting cho lesterol efflux to ApoA-I concentrations, Therefore, the relative efflux po tential reflects the relative efficiency of ApoA-I in determining cell chol esterol efflux, The relative efflux potential of mouse and human sera was i n the following order: A-I-M mice>A-I-M carriers>A-I-WT mice = control subj ects, suggesting a gene-dosage effect of the A-I-M mutation on the efficien cy of serum to extract cholesterol from cells. The high efficiency of A-I-M -containing HDL for cell cholesterol uptake would result in an improved rev erse cholesterol transport in the A-I-M carriers, possibly explaining the l ow susceptibility to atherosclerosis development.