VLDL AND IDL APOLIPOPROTEIN B-100 KINETICS IN FAMILIAL HYPERCHOLESTEROLEMIA DUE TO IMPAIRED LDL RECEPTOR FUNCTION OR TO DEFECTIVE APOLIPOPROTEIN B-100

Mutations in the apolipoprotein (ape) B, E (LDL) receptor gene and in the apolipoprotein B-100 gene are the cause of familial hypercholester olemia (FH) and of familial defective apo B-100 (FDB), respectively Wh ether these abnormalities lead to altered production or uptake of very low density lipoprotein (VLDL) or intermediate density lipoprotein (I DL) has not been established previously. Therefore VLDL and IDL apo B- 100 kinetics were measured in seven subjects with FH, in six subjects with FDB, and in five normo-cholesterolemic controls using primed-cons tant infusions of [1-C-13]leucine. Absolute production rates (APR) of VLDL apoB were higher in FH than in controls (27.1 +/- 1.9 vs. 17.9 +/ - 2.1 mg/kg/day P < 0.03). VLDL APR in FDB were between those of FH an d controls (24.3 +/- 4.8 mg/kg/day), and demonstrated a relatively lar ge inter-individual variability. The increase in VLDL APR in FH result ed in higher fasting serum triglyceride concentrations than in control s (P < 0.05), whereas in FDB triglycerides were between those observed in FH and in controls. A significant correlation was observed be twee n VLDL apoB APR and serum triglycerides in FH and in FDB; the correlat ion coefficient for all subjects was r = 0.84 (P < 0.0001), indicating that the major determinant of serum triglyceride concentrations was V LDL apoB APR. IDL apoB APR was lower in FH and in FDB compared to cont rols (P < 0.03 P < 0.02, respectively): and its fractional catabolic r ate (FCR) was slightly lower in FH and in FDB, resulting in similar pl asma IDL apoB concentrations in all three groups of subjects. IDL apoB APR in FH were negatively correlated with LDL cholesterol concentrati ons (r = -0.89; P < 0.001); LDL cholesterol concentrations correlated positively with the part of VLDL that did not appear in IDL (r = 0.82 P < 0.02), bypassing therefore the delipidation cascade. In conclusion the data demonstrate increased VLDL apoB production rates in FH. VLDL and IDL kinetics differ when LDL concentrations are elevated either d ue to a LDL receptor defect or due to defective apolipoprotein B-100.