INCREASED SITOSTEROL ABSORPTION IS OFFSET BY RAPID ELIMINATION TO PREVENT ACCUMULATION IN HETEROZYGOTES WITH SITOSTEROLEMIA

Using plasma isotope-kinetic methods, we measured the absorption and turnover rates of cholesterol and sitosterol (24-ethylcholesterol) in two obligate heterozygotes (parents) and their homozygous daughter with sitosterolemia with xanthomatosis. Diets contained approximately 500 mg/day cholesterol and 100 mg/day sitosterol. In the homozygote, plasma cholesterol and apolipoprotein B concentrations were slightly higher, but sitosterol levels were 22 and 58 times higher than in her heterozygous parents. Cholesterol absorption was at the high end of the normal range in both heterozygotes (59% and 84%) and in the homozygote (62%) (value in the control subject 48%). In contrast, cholesterol synthesis was severely depressed in the homozygote (28% and 26% as great as in the heterozygotes and the control, respectively). Sitosterol absorption in the homozygote (34%) was 2.3 and 2.0 times greater than in the heterozygotes and 6.8 times greater than in the control. The sitosterol turnover rate, calculated independently by mathematical analysis of specific-activity decay curves, amounted to 15 and 24 mg/day in the heterozygotes compared with 27 mg/day in the homozygote and 7.9 +/- 2.3 mg/day in five control subjects. However, the total body sitosterol pool was 15 and 10.3 times larger in the homozygote (4,080 mg) than in her heterozygous parents because of extremely slow removal. The average sitosterol elimination constant in the heterozygotes (K(A) = 0.11 day-1) was 10 times that in the homozygote (K(A) = 0.01 day-1) but 35% less than that in the controls (K(A) = 0.17 day-1). These results demonstrate that despite enhanced sitosterol absorption, small body pools and low plasma concentrations result from rapid elimination associated with adequate cholesterol synthesis in sitosterolemic heterozygotes. In distinction, sitosterol accumulates and body pools are disproportionately enlarged because increased absorption is combined with decreased removal, which may compensate for reduced cholesterol synthesis in sitosterolemic homozygotes.