Hypo- and hyperresponse of serum cholesterol level and low density lipoprotein production and degradation to dietary cholesterol in man.

Serum cholesterol in man rises when cholesterol intake increases, but the extent of the elevation varies between subjects. Part of the variation between subjects is spurious and not reproducible; it is caused by random diet-independent fluctuations of serum lipid levels. Part is due to consistent metabolic differences between subjects. We have earlier found that responsiveness was associated with higher initial total and HDL cholesterol, lower habitual cholesterol consumption, and lower body mass index, and unrelated to gender, age, or apo E phenotype. We have now investigated the metabolic basis of variability by measuring turnover rates of low density lipoprotein (LDL) apolipoprotein B (apo B) on a low-cholesterol diet (140 mg/day) and a high-cholesterol diet (900 mg/day) in 8 volunteers with well-defined differences in the responsiveness of their serum cholesterol to diet. Autologous 125I-LDL was injected on day 23 of each diet period. Its fractional catabolic rate (FCR) was estimated from the ratio of 125I in urine over that in plasma, seven days after injection. FCR (mean +/- SD) increased from 0.24 +/- 0.02 pools/day on the low- to 0.31 +/- 0.20 on the high-cholesterol diet. LDL-apo B concentration rose from 49 +/- 13 to 63 +/- 12 mg/dl, and LDL-apo B production rate, calculated as FCR x concentration/body weight, from 4.8 +/- 1.2 to 8.0 +/- 1.4 mg/kg/day. The individual rise in production rate was significantly correlated with the rise in the serum concentration of LDL-apo B (r = 0.90) or LDL-cholesterol (r = 0.75), and also with the rise in total serum cholesterol measured in these same subjects in similar experiments 3-4 years earlier (r = 0.74). Degradation of LDL by freshly isolated blood mononuclear cells and by mononuclear cells incubated for 72 h in lipoprotein-deficient medium (derepressed cells) was measured on both diets in these and in additional volunteers. The rate of degradation (mean +/- SD) of standard human LDL by fresh cells was 336 +/- 166 ng LDL protein/mg cell protein per 8 h on the low-cholesterol diet, and decreased by 147 +/- 180 ng/mg per 8 h or 44% on the high-cholesterol diet (n = 23, p < 0.01). The catabolic activity of derepressed cells obtained when subjects were on the low-cholesterol diet was negatively related to the LDL cholesterol response (r = -0.57, n = 18, p < 0.05), and to the total cholesterol response in earlier experiments (r = -0.45, n = 18, p < 0.10).(ABSTRACT TRUNCATED AT 400 WORDS)