ADENOVIRAL DELIVERY OF LOW-DENSITY-LIPOPROTEIN RECEPTORS TO HYPERLIPIDEMIC RABBITS - RECEPTOR EXPRESSION MODULATES HIGH-DENSITY-LIPOPROTEINS

Plasma concentrations of low-density lipoproteins (LDLs) and high-dens ity lipoproteins (HDLs) are inversely related in several dyslipoprotei nemias. To elucidate the interactions between these lipoproteins, we u sed a recombinant adenovirus (hLDLR-rAdV) to express human LDL recepto rs (hLDLRs) in LDL receptor-deficient rabbits. hLDLR-rAdV administrati on resulted in hepatocyte expression and a reduction of total, interme diate density lipoprotein (IDL), and LDL cholesterol. In addition, we found that hLDLR-rAdV treatment induced (1) increased very-low-density lipoprotein (VLDL) cholesterol, (2) increased VLDL, IDL and LDL trigl ycerides, (3) decreased alpha- and pre-beta-migrating apolipoprotein E (apo E) and decreased pre-beta-migrating apo A-I at 2 to 4 days postt reatment, and (4) increased total plasma apo A-I and pre-beta-migratin g apo A-I beginning 8 to 10 days posttreatment. Virtually all plasma a po A-I was present on alpha- and pre-beta-HDL. Pre-beta-HDL particles with size and electrophoretic properties consistent with nascent HDL d emonstrated the greatest relative apo A-I enrichment following hLDLR-r AdV treatment. In summary, enhanced expression of hepatocyte LDLRs by hLDLR-rAdV treatment markedly altered apo A-I-containing lipoproteins and IDL and LDL. The use of recombinant viruses to express physiologic ally relevant genes in intact animals, analogous to transfection of ce lls in culture, provides a new strategy for the evaluation of effects of specific gene products on metabolic systems in vivo. Copyright (C) 1996 by W.B. Saunders Company