Overproduction of a buoyant low density lipoprotein subspecies in spontaneously hypercholesterolemic mutant pigs

We previously described the hypercholesterolemia of pigs with defined apolipoprotein B (apo B) alleles associated with reduced binding of low density lipoprotein (LDL) to its receptor in vitro and slow clearance from the circulation in vivo. The increased plasma LDL in the hypercholesterolemic pigs was confined to a buoyant LDL subspecies. Because of this qualitative change in the LDL subspecies profile, we studied the turnover of buoyant and dense LDL subspecies independently. Normal and mutant radioiodinated buoyant and dense LDLs were simultaneously injected into normal and mutant pigs, and the clearance rates, interconversion rates, and production rates were determined. The sevenfold increase in buoyant LDL levels in the mutant pigs was due to a fivefold increase in buoyant LDL production. Total mutant LDL production was increased approximately 25%, suggesting that part of the increase in buoyant LDL production is at the expense of dense LDL production. Conversion of dense LDL to buoyant LDL made a small contribution to the buoyant LDL increase. The turnover analysis showed that dense LDL, in both mutant and control pigs, is primarily derived from a source other than buoyant LDL. To test this more directly, [3H]leucine was intravenously injected, and the specific activity of the LDL subspecies was measured over 96 hours. There was a large discrepancy in the areas under the specific activity-versus-time curves, indicating that buoyant LDL cannot be the sole precursor of dense LDL and further supporting the conclusion that buoyant and dense LDL are, in part, metabolically independent particles. These results show that genetic variation in the apo B locus can affect the synthetic rate of LDL and the LDL subspecies distribution.