Apoprotein B-100 Production Is Decreased in Subjects Heterozygous for Truncations of Apoprotein B

Abstract

Abstract Among individuals who are heterozygous for familial hypobetalipoproteinemia (FHBL) and who have various truncations of apoprotein (apo) B (ie, FHBL with apoB truncation/apoB-100 genotypes), the plasma concentrations of apoB-100 are typically ≈30% rather than the expected ≈50% of those in unaffected family members. The metabolic basis for the low apoB-100 levels is unknown. Therefore, we compared the metabolism of apoB-100 in 8 subjects with heterozygous FHBL (2 apoB-89/apoB-100, 2 apoB-75/apoB-100, 2 apoB-54.8/apoB-100, 1 apoB-52/apoB-100, and 1 apoB-31/apoB-100) with the metabolism of apoB-100 in 8 apoB-100/apoB-100 control subjects who were paired with the heterozygotes by gender, age, height, weight, and race. Endogenous labeling of apoB-100 with [ 13 C]leucine and a multicompartmental kinetic model were used to obtain kinetic parameters. FHBL heterozygotes had significantly reduced VLDL apoB-100 production rates (7.7±3.7 versus 21.2±6.2 mg · kg −1 · d −1 , P =.002) and LDL apoB-100 production rates (4.5±3.12 versus 15.3±1 mg · kg −1 · d −1 , P =.05) compared with control subjects. Fractional conversion rates of VLDL to LDL were not significantly different (0.67±0.36 versus 0.77±0.17 pools/d), and the respective fractional catabolic rates of apoB-100 in VLDL, IDL, and LDL also were similar in both groups. Thus, FHBL heterozygotes produced apoB-100 at about 30% of the rates of control subjects. We believe these reduced production rates largely account for the lower than expected levels of apoB-100 and LDL cholesterol in the plasma of FHBL heterozygotes.