Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins.
The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mulder
M
M
TNO Institute of Prevention and Health Research, Gaubius Laboratory, Leiden, The Netherlands.
van der Boom
H
H
de Knijff
P
P
Braam
C
C
van den Maagdenberg
A
A
Leuven
J A
JA
Havekes
L M
LM
D000483:Alleles; D000818:Animals; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics*; D001667:Binding, Competitive; D002784:Cholesterol / Q000378:metabolism*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000235:genetics* / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D010641:Phenotype; D014280:Triglycerides / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D053329:Apolipoprotein E2; D001057:Apolipoproteins E; D008074:Lipoproteins; D014280:Triglycerides; C030104:lipoprotein cholesterol; C030087:lipoprotein triglyceride; D002784:Cholesterol