LDL-CHOLESTEROL, APOB100 KINETICS AND ATHEROSCLEROSIS IN LDLR-DEFICIENT YUCATAN MINIPIGS: A NEW MODEL FOR FAMILIAL HYPERCHOLESTEROLEMIA

Lack of animal models with human-like lipoprotein metabolism and lesion pathology has hampered translational research in atherosclerosis. Recently, a model of familial hypercholesterolemia was developed in Yucatan miniature pigs, in which the LDL receptor (LDLR) was deleted through gene targeting of exon 4. The objective of the present study was to determine the plasma lipoprotein response to a high fat diet, the kinetics of apolipoprotein (apo) B metabolism and atherosclerosis in LDLR-deficient miniature pigs. LDLR+/+ (n=5), LDLR+/- pigs (n=6) and LDLR-/- pigs (n=5) were fed a diet containing 34% kcal from fat and 0.2% cholesterol (C). At 6 weeks, kinetics of plasma apoB100 (fasting) were measured using stable isotopic techniques and multi-compartmental modeling. In chow-fed pigs, LDL-C was 0.8mM, 1.3mM and 14mM in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. On diet for 6 weeks, LDL-C increased 1.3-fold (to 1.09mM), 1.7-fold (to 2.3mM) and 1.2-fold (to 15.8mM) in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. The effect of genotype or diet on plasma TG and HDL-C was modest. Compared to LDLR+/+ pigs, VLDL apoB100 pool sizes increased 1.4-fold in LDLR+/- and 1.7-fold in LDLR-/- pigs, due primarily to a decrease in fractional catabolic rates (FCR) of 18% and 63%, respectively. Compared to LDL+/+ pigs, LDL apoB100 pool sizes increased 2.2-fold and 14-fold in LDLR+/- and LDLR-/-, respectively, which was due to both 1.5-fold and 2-fold increases in production rates and 24% and 85% decreases in FCR, respectively. At 23 weeks, raised lesion area in the abdominal aorta was 3.3% in LDLR+/- pigs and 48.5% in LDLR-/- pigs. In standardized histological sections the left anterior descending coronary artery, lesion area was 1,4746 μm2 in LDLR+/- pigs and 533,257 μm2 in LDLR-/- pigs. This model will prove useful for translational research in lipoprotein metabolism and atherosclerosis.