RECENT INSIGHTS INTO THE PATHOGENESIS OF TYPE-III HYPERLIPOPROTEINEMIA

Type III hyperlipoproteinemia is a genetic disorder of lipoprotein metabolism characterized by high plasma cholesterol and triglycerides, the presence of a characteristic lipoprotein termed beta-very low density lipoprotein (beta-VLDL), xanthomatosis, and premature atherosclerosis. Defects in the gene for apolipoprotein (apo) E represent the molecular cause of this disorder. ApoE serves as a ligand for the receptor-mediated clearance of the triglyceride-rich lipoproteins from the circulation. All defects in apoE cause impaired lipoprotein clearance through the same mechanism, that is, the disruption, either direct or indirect, of the receptor-binding region of the apoE molecule. However, the receptor-binding defect alone does not fully explain the pathogenesis of beta-VLDL formation, the development of type III hyperlipoproteinemia, and its mode of inheritance, which can be either recessive or dominant, depending on the apoE mutation. Recent studies suggest that other functional properties of apoE might play a role in the formation of beta-VLDL. Modulation of the receptor-binding defect, association with VLDL, heparin-binding affinity, and interaction with lipolytic enzymes could all contribute to the expression of the disease phenotype and determine its mode of inheritance.