Familial combined hyperlipidemia (FCHL) is a dominantly-inherited disorder of lipoprotein metabolism which occurs with a frequency of 1 in 200 in the population and is expressed as variable patterns of plasma lipid elevations. It is responsible for a major proportion of the morbidity and mortality associated with premature coronary artery disease in the U.S. The underlying metabolic defect in this disorder is unknown. The long term objectives of this research are: 1) to identify a genetic marker for FCHL which will permit a definitive diagnosis, even in children in whom the hyperlipidemia of FCHL is usually unexpressed; and 2) to provide a method for assessing the effects of therapeutic intervention in FCHL patients. This project for the first time proposes to apply stable isotope methodology, recently adapted to the study of lipoprotein metabolism, to the elucidation of the metabolic defect in FCHL. Previous studies by others using existing methodology have suggested that FCHL may be primarily due to overproduction of the apolipoprotein Beta of very low density lipoprotein (VLDL-apoBeta). The proposed studies, which utilize steady state labeling of the VLDL-apoBeta with 15N-glycine, have been designed to focus on VLDL-apo3 synthesis and to allow simpler calculation of synthetic rates than was possible with previous methods.
The specific aims of the proposal are: 1) to establish normal values for the fractional and absolute synthetic rates of VLDL-apoBeta in adults and children using steady state labeling with stable isotopes; 2) to determine if overproduction of VLDL-apoBeta is a common feature of unrelated subjects with FCHL; 3) to determine if overproduction of VLDL-apoBeta is a constant finding in affected members of a family with FCHl regardless of the expressed lipoprotein phenotype; and 4) to determine if excess production of VLDL-apoBeta is a genetic marker for FCHL that precedes hyperlipidemia in children. The safety of stable isotope techniques permits repeated studies on the same subjects to assess the effects of therapeutic intervention and, for the first time, allows the study of children at risk for FCHL.
