Marked elevation in serum apolipoprotein E in a case of heterozygous cholesteryl ester transfer protein deficiency

The subject was a 57-year-old Japanese woman with a body mass index of 21.2 kg m −2. Her serum total cholesterol (TC), triglycerides (TG) and HDL-cholesterol levels were 7.11 mmol l −1, 0.53 mmol l −1 and 2.05 mmol l −1, respectively. She had a marked increase of serum apolipoprotein (Apo) E concentration of 25 mg dl −1 with normal concentrations of serum Apo A-I, A-II, B, C-II and C-III. Polymerase chain reaction–restriction fragments length polymorphism analysis of the cholesteryl ester transfer protein (CETP) gene from this subject revealed the heterozygous nucleotide change causing a Asp442 to Gly substitution (D442G) in the CETP protein. For comparison, 11 unrelated female subjects with this mutation (age, 57±5.1 years; BMI, 22±1.5 kg m −2; TC, 7.23±1.16 mmol l −1; TG, 1.44±0.80 mmol l −1; HDL-C, 2.47±0.53 mmol l −1) were found to have a serum Apo E concentration of 7±1.5 mg dl −1, about a third of the patient’s concentration. The lipoprotein profile of the proband’s serum analyzed by disk polyacrylamide gel electrophoresis showed a trace amount of VLDL. A vitamin A fat-loading test showed little increase in serum triglycerides and retinyl palmitate levels compared with control subjects at 2, 4 and 6 h after fat loading. Ultracentrifugation analysis of her serum revealed no detectable Apo E in the VLDL fraction but showed a large amount of Apo E in the HDL fraction, in contrast to a normal control, who had Apo E in the VLDL fraction as well as in the HDL fraction. Sequence analysis of the Apo E gene from the subject showed no nucleotide changes in exon 3 and exon 4, which code the mature Apo E protein, indicating there is no structural abnormality in the Apo E protein. Direct sequence analysis of the LDL receptor gene also did not show any nucleotide change. Based on these findings, it was hypothesized that the marked increase of Apo E in the patient’s serum was caused by a decreased transfer of Apo E from HDL particles to TG-rich lipoproteins or impaired uptake of Apo E-containing HDL by LDL receptor or remnant receptor, due presumably to a dysfunction of these receptors in the patient.