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 associated with homozygosity for the apolipoprotein (apo) E-2 allele. Factors 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 vitro the interaction of apoE with LPL was analyzed in cell binding assays. All type III HLP patients showed delayed triglyceride (TG) clearance and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparable to apoE3/3 controls. HLP patients showed lower LPL activity and mass than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mutation in three patients and a -93 T-G substitution combined with an Asp 9-->Asn mutation in one control subject. In addition to LPL abnormalities, postprandial hyperinsulinemia was observed in five out of eight patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven out 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 manifestation of type III HLP. Hyperinsulinemia appears to be an additional factor important for disease expression.
Brümmer
D
D
Medizinische Klinik, Universitätskrankenhaus Eppendorf, Hamburg, Germany.
Evans
D
D
Berg
D
D
Greten
H
H
Beisiegel
U
U
Mann
W A
WA
D000328:Adult; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002460:Cell Line; D004224:Diterpenes; D005215:Fasting; D005260:Female; D005347:Fibroblasts; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood*; D006952:Hyperlipoproteinemia Type III / Q000097:blood* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D019518:Postprandial Period / Q000502:physiology*; D000084562:Retinyl Esters; D014801:Vitamin A / Q000031:analogs & derivatives / Q000097:blood
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D001786:Blood Glucose; D004224:Diterpenes; D008055:Lipids; D008079:Lipoproteins, VLDL; D000084562:Retinyl Esters; D014801:Vitamin A; C014794:retinol palmitate; D008071:Lipoprotein Lipase