Metabolic heterogeneity of low density lipoprotein-apoB production in familial hypercholesterolemia: an analytical model solution of tracer data.

Abstract

Six subjects with heterozygous familial hypercholesterolemia (FH) (three males, three females) formed the basis for an investigation of the pathways of production of apoprotein B within plasma low-density-lipoprotein (LDL-apoB). Following the intravenous injection of [75Se]selenomethionine as an amino acid tracer, incorporation of the radioactive isotope into the putative precursor of LDL, intermediate density lipoprotein (IDL-apoB), was examined over a 9-day period. The resulting tracer data provided the precursor profile for both the IDL catabolic conversion of LDL as well as for direct synthesis of LDL from amino acids. The fractional conversion rates, (beta) for IDL and (alpha) for amino acids to LDL-apoB, were determined utilizing the two-compartment model for LDL involving both the intravascular and the extravascular pools of apoB. This LDL model was resolved analytically and the parameters alpha and beta were determined so as to give the least squares fit to the LDL tracer data. In this solution, the fractional conversion rates of IDL and of amino acids to LDL-apoB were resolved with a mean fractional residual of 20 +/- 6%, which was randomly distributed within the LDL-apoB data throughout the 216 hours of the studies. The steady-state determination of the pathways of LDL-apoB synthesis, based upon this tracer analysis, indicate that IDL accounts for 46%, and amino acids account for 54% of total apoB production within plasma LDL in heterozygous FH. In contrast, in normal subjects, IDL accounts for 86% of total LDL-apoB production. Since the IDL catabolic pathway represents the predominant if not exclusive source of LDL in normal man, this demonstration of a major non-IDL source of LDL in FH broadens the understanding of the pathophysiology of human familial hypercholesterolemia.