EXPRESSION OF HUMAN APOLIPOPROTEIN-B AND ASSEMBLY OF LIPOPROTEIN(A) IN TRANSGENIC MICE

The atherogenic macromolecule lipoprotein(a) [Lp(a)] has resisted in v ivo analyses partly because it is found in a limited number of experim ental animals. Although transgenic mice expressing human apolipoprotei n (a) [apo(a)l have previously been described, they failed to assemble Lp(a) particles because of the inability of human apo(a) to associate with mouse apolipoprotein B (apoB). We isolated a 90-kilobase P1 phag emid containing the human apoB gene and with this DNA generated 13 lin es of transgenic mice of which 11 expressed human apoB. The human apoB transcript was expressed and edited in the liver of the transgenic mi ce. Plasma concentrations of human apoB, as well as low density lipopr otein (LDL), were related to transgene copy number; the transgenic lin e with the most copies of human apoB had a >4-fold increase in LDL cho lesterol compared with nontransgenics and a lipoprotein profile simila r to that of humans. When human apoB and apo(a) transgenic mice were b red together, plasma apo(a) in mice expressing both human proteins was tightly associated with lipoproteins in the LDL density region. These studies demonstrate the successful expression of human apoB and the e fficient assembly of Lp(a) in mice.