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-cho lesterol 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 con centration of 35 mg dl(-1) with normal concentrations of serum Apo A-I, A-I I, B, C-II and C-III. Polymerase chain reaction-restriction fragments lengt h polymorphism analysis of the cholesteryl ester transfer protein (CETP) ge ne 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); H DL-C, 2.47 +/- 0.53 mmol l(-1)) were found to have a serum Apl, E concentra tion of 7+/-1.5 mg dl(-1), about a third of the patient's concentration. Th e lipoprotein profile of the proband's serum analyzed by dish polyacrylamid e Eel electrophoresis showed a trace amount of VLDL. A vitamin A fat-loadin g test showed little increase in serum triglycerides and retinyl palmitate levels compared with control subjects at 2, 4 and 6, h after fat loading. U ltracentrifugation analysis of her serum revealed no detectable Apo E in th e VLDL fraction but showed a lar ge amount of Apo E in the HDL fraction, in contrast to a normal control, who had Apo E in the VLDL fraction as well a s 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 cede the mature A po E protein, indicating there is no structural abnormality in the Apo E pr otein. Direct sequence analysis of the LDL receptor gene also did not show any nucleotide change. Based on these findings, it was hypothesized that th e 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 u ptake of Apo E-containing HDL by LDL receptor or remnant receptor, due pres umably to a dysfunction of these receptors in the patient. (C) 2000 Elsevie r Science B.V. All rights reserved.