Significant cholesterol synthesis occurs in gut mucosa of animals and humans. However, the role of gut synthesis in hypercholesterolemia and the effect of drugs on this function have not been defined. We obtained jejunal biopsies and bile samples from 21 Type II hypercholesterolemic subjects (mean serum cholesterol = 331 mg/dl) on a low fat diet after an overnight fast. Whole gut mucosal homogenate was assayed for activity of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-determining enzyme of cholesterol synthesis. Mean reductase activity (pmol/mg per min) was 5.5 ± 1.0 (n = 21) in hypercholesterolemic subjects versus 11.3 ± 1.0 in 52 normal subjects (P < 0.01). This is consistent with the hypothesis that the primary defect in these patients is not excessive cholesterol synthesis but decreased low density lipoprotein (LDL) clearance. It implies that high LDL levels down-regulate gut reductase activity. After treatment of 7 patients with lovastatin (40-80 mg/day for at least 6-13 weeks), gut reductase activity decreased from 7.7 ± 2.6 to 3.6 ± 0.5 (P < 0.05), in biopsies obtained 12 hr after the last drug dose. Inhibition of reductase activity by this drug was detected 12 hr after a dose, and the enzyme was not measurably induced during 6-13 weeks of therapy. In keeping with the decrease in serum cholesterol (332 → 239 mg/dl) and mucosal reductase activity during lovastatin therapy, mean gallbladder bile cholesterol saturation index also decreased (1.045 ± 0.112 vs 0.883 ± 0.109, n = 7). During treatment with cholestyramine (16-24 g/day for ≥ 8 weeks), gut reductase tended to increase (4.7 ± 1.0 vs 10.4 ± 3.9 pmol/mg per min), consistent with its effect on cholesterol synthesis in animal studies, but the changes did not reach statistical significance. We conclude that intestinal cholesterol synthesis is low in Type II hypercholesterolemic patients and is modified by lovastatin.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of lipid research|
|State||Published - 1988|