APOPROTEIN-B-100 PRODUCTION IS DECREASED IN SUBJECTS HETEROZYGOUS FOR TRUNCATIONS OF APOPROTEIN-B

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 approximate to 30% rather than the expected approximate to 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 [C-13]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.