APOLIPOPROTEIN-B AND A 2ND MAJOR GENE LOCUS CONTRIBUTE TO PHENOTYPIC VARIATION OF SPONTANEOUS HYPERCHOLESTEROLEMIA IN PIGS

The Lpb(5) apolipoprotein B (apoB) allele occurs in pigs with spontane ous hypercholesterolemia. Low-density lipoprotein (LDL) from these pig s binds to the LDL receptor with a lower affinity and is cleared from the circulation more slowly than control pig LDL. However, the severit y of hypercholesterolemia in pigs with the mutant apoB allele is highl y 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). LD L from both Lpb5.1 and Lpb5.2 pigs was catabolized in vivo and in vitr o at a similarly reduced rate. The difference in plasma cholesterol be tween the two phenotypic groups was in part due to a higher buoyant LD L 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 chemi cally modified to abrogate LDL receptor binding. Approximately 50% of LDL clearance in normal and Lpb5.2 pigs was via the LDL receptor; in L pb5.1 pigs, 100% of LDL clearance was LDL receptor independent. Quanti tative pedigree analysis of the segregation of the plasma cholesterol phenotype suggested that two major gene loci (the apoB locus and a sec ond apparently unlinked locus) contribute to the determination of plas ma cholesterol levels in this pig population.