We examined low density lipoprotein (LDL) receptor activities of 13 heterozygous patients with familial hypercholesterolemia (FH) using peripheral lymphocytes.
The receptor activities were measured as the degradation of 125I-labeled LDL in lymphocytes which had been cultured for three days in 10% lipoprotein-deficient serum. After incubation, 10μg/ml of 125I-LDL were added to the medium in the presence or absence of 250μg/ml of nonlabeled LDL and then the lymphocytes were incubated for five hours further. The radioactivity of the trichloroacetic acid-soluble fraction of the medium was measured.
As a result, LDL receptor activities of FH heterozygotes were revealed to correlate significantly and negatively with serum LDL-cholesterol concentration. If we combined them with those of two FH homozygotes and 18 hyperlipidemic patients other than FH and normolipidemic persons, the latter of which we reported previously (J. Jpn. Atheroscler. Soc. 12: 303-308, 1984), not only the grade of the negative correlation between LDL receptor activities and LDL-cholesterol became greater, but LDL receptor activities also correlated negatively with total cholesterol (TC) (p<0.01). Extrapolation from these data suggested that LDL receptor activity would disappear when TC concentration was higher than 718mg/dl. The value estimated agreed well with the clinical findings of FH.
Then, probucol (750mg a day) was administered to eight heterozygous patients with FH for four to six months, by which TC concentration decreased significantly from 319.6±36.7 (mg/dl) to 282.3±17.4 (mg/dl). The result suggests that probucol is effective in the treatment of FH. The levels of LDL receptor activities in the pretreatment state was not correlated to the effectiveness of probucol treatment in each case.
LDL receptor activities were also measured after probucol administration and were compared with those of the pretreatment state. There were a great variations of change of LDL receptor activity among the eight patients, and no definite trend of the activity could be found. But, it was suggested that the percentage change of TC concentration was correlated negatively with the difference in LDL receptor activity before and after probucol administration, that is, the more the TC concentration decreased, the more the LDL receptor activity increased.
These results may suggest that the main action of probucol is not on LDL receptor and probucol indirectly influences LDL receptor activity by the change in serum cholesterol concentration.
