TRANSGENIC MICE EXPRESSING HIGH PLASMA-CONCENTRATIONS OF HUMAN APOLIPOPROTEIN B100 AND LIPOPROTEIN(A)

The B apolipoproteins, apo-B48 and apo-B100, are key structural protei ns in those classes of lipoproteins considered to be atherogenic [e.g. , chylomicron remnants, beta-VLDL, LDL, oxidized LDL, and Lp(a)]. Here we describe the development of transgenic mice expressing high levels of human apo-B48 and apo-B100. A 79.5-kb human genomic DNA fragment c ontaining the entire human apo-B gene was isolated from a PI bacteriop hage library and microinjected into fertilized mouse eggs. 16 transgen ic founders expressing human apo-B were generated, and the animals wit h the highest expression had plasma apo-B100 levels nearly as high as those of normolipidemic humans (approximately 50 mg/dl). The human apo -B100 in transgenic mouse plasma was present largely in lipoproteins o f the LDL class as shown by agarose gel electrophoresis, chromatograph y on a Superose 6 column, and density gradient ultracentrifugation. Wh en the human apo-B transgenic founders were crossed with transgenic mi ce expressing human apo(a), the offspring that expressed both transgen es had high plasma levels of human Lp(a). Both the human apo-B and Lp( a) transgenic mice will be valuable resources for studying apo-B metab olism and the role of apo-B and Lp(a) in atherosclerosis.