Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs

The Lpb⁵ apolipoprotein B (apoB) allele occurs in pigs with spontaneous hypercholesterolemia. Low-density lipoprotein (LDL) from these pigs binds to the LDL receptor with a lower affinity and is cleared from the circulation more slowly than control pig LDL. However, the severity of hypercholesterolemia in pigs with the mutant apoB allele is highly variable. This study aimed to determine the metabolic basis for the phenotypic heterogeneity among Lpb5 pigs. Lpb5 pigs were divided into two groups: those with plasma cholesterol greater than 180 mg/dL (Lpb5.1) and those with plasma cholesterol less than 180 mg/dL (Lpb5.2). LDL from both Lpb5.1 and Lpb5.2 pigs was catabolized in vivo and in vitro at a similarly reduced rate. The difference in plasma cholesterol between the two phenotypic groups was in part due to a higher buoyant LDL production rate in Lpb5.1 pigs than in Lpb5.2 pigs. The in vivo LDL receptor status was evaluated by measuring the catabolism of LDL chemically modified to abrogate LDL receptor binding. Approximately 50% of LDL clearance in normal and Lpb5.2 pigs was via the LDL receptor; in Lpb5.1 pigs, 100% of LDL clearance was LDL receptor independent. Quantitative pedigree analysis of the segregation of the plasma cholesterol phenotype suggested that two major gene loci (the apoB locus and a second apparently unlinked locus) contribute to the determination of plasma cholesterol levels in this pig population.