Decreased Production and Increased Catabolism of Apolipoprotein B-100 in Apolipoprotein B-67/B-100 Heterozygotes

Abstract

Abstract Apolipoprotein (apo) B-67 is a truncated form of apoB-100 due to deletion of an adenine at cDNA 9327. Heterozygotes have one allele making apoB-100; therefore, plasma apoB levels would be predicted to be at least 50% of normal. However, apoB-67 heterozygotes have total plasma apoB levels that are 24% of normal. To determine the mechanisms responsible for the lower-than-expected levels of apoB, in vivo kinetics of apoB-100 were performed in three apoB-67/apoB-100 heterozygotes and compared with those of six control subjects by using a primed-constant infusion of [5,5,5- 2 H 3 ]leucine in the fed state. Kinetic parameters were calculated by multicompartmental modeling of the data. The mean total apoB plasma concentration of the apoB-67 subjects was 21.8±6.1 mg/dL, or 24% of that of control subjects (89.6±24.1 mg/dL, P =.002). ApoB-67 subjects had lower mean VLDL apoB-100 production rates (3.6±1.2 versus 13.9±3.5 mg·kg −1 ·d −1 , P =.002) and lower mean transport rates of apoB-100 into LDL (3.5±1.4 versus 12.6±4.1 mg·kg −1 ·d −1 , P =.008) compared with control subjects. The transport rate into IDL was not significantly different (1.2±0.5 versus 6.2±4.0 mg·kg −1 ·d −1 , P =.07). The fractional catabolic rate of VLDL apoB-100 was significantly higher in apoB-67 subjects than in control subjects (18.1±8.6 versus 7.6±1.6 mg·kg −1 ·d −1 , P =.017). ApoB-100 IDL and LDL fractional catabolic rates were not significantly different. VLDL apoB-100 pool size in apoB-67 subjects was 11% of that of control subjects (15.8±7.7 versus 141.6±33.7 mg, P =.0004) due to a 74% lower production rate (26% of control values) and a 2.4-fold higher fractional catabolic rate. LDL apoB-100 pool size in apoB-67 subjects was 22% of that of control subjects (665.3±192.4 versus 2968.3±765.2 mg, P =.002) due primarily to a lower production rate (27% of control values). Thus, both decreased production of VLDL and LDL apoB-100 and increased catabolism of VLDL apoB-100 are responsible for the low levels of apoB-100 in apoB-67 subjects.