EXPRESSION OF TYPE-III HYPERLIPOPROTEINEMIA IN PATIENTS HOMOZYGOUS FOR APOLIPOPROTEIN E-2 IS MODULATED BY LIPOPROTEIN-LIPASE AND POSTPRANDIAL HYPERINSULINEMIA

Type III hyperlipoproteinemia (HLP) is a multifactorial disorder assoc iated with homozygosity for the apolipoprotein (ape) E-2 allele. Facto rs which may promote the development of HLP include lipoprotein lipase (LPL) and hyperinsulinemia. These factors were investigated in eight patients with type III HLP and in nine normolipidemic controls. In vit ro the interaction of apoE with LPL was analyzed in cell binding assay s. All type III HLP patients showed delayed triglyceride (TG) clearanc e and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparab le to apoE3/3 controls. HLP patients showed lower LPL activity and mas s than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mu tation in three patients and a -93 T-G substitution combined with an A sp 9-->Asn mutation in one control subject. In addition to LPL abnorma lities, postprandial hyperinsulinemia was observed in five out of eigh t patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven o ut of eight patients with type III HLP showed LPL abnormalities and/or postprandial hyperinsulinemia. Together with the in vitro data these findings support a coordinate effect of apoE and LPL for the manifesta tion of type III HLP. Hyperinsulinemia appears to be an additional fac tor important for disease expression.