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 t he 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 rat ios 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 l ipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ra tio of the d < 1.019 g/ml lipoprotein fraction in these FD patients in creased only marginally (from 0.8 to 1.1), as compared with that of cl assical FD subjects (from 1.4 to 2.6) and non-FD control subjects (fro m 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(Lys14 6 --> Gln) carriers, possibly in combination with a less efficient cho lesteryl ester transfer protein (CETP) activity, blood samples of APOE ()2(Lys146 --> Gln) allele carrying FD patients were analysed and com pared with classical FD patients and controls. In the APOE()2(Lys146 --> Gin) FD patients, the increase in plasma cholesterol was mainly co nfined 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 (ra tios 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 all ele carriers is 3.5 times as high as that found in non-carriers (2.8 v s. 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 fra ction of APOE()2(Lys146 --> Gln) FD patients to compete with low dens ity 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) a llele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP ac tivity. As a consequence, this might result in a less efficient cellul ar processing of these lipoproteins via the LDL receptor and in this w ay explain the dominant behaviour of the APOE()2(Lys146 --> Gln) alle le in the expression of FD.