Journal of Lipid Research, Vol 29, 839-845, Copyright © 1988 by Lipid Research, Inc.
Intestinal HMG-CoA reductase activity is low in hypercholesterolemic patients and is further decreased with lovastatin therapy
ML Freeman, WF Prigge, DB Hunninghake, WC Duane and RL Gebhard
Department of Medicine, VA Medical Center, Minneapolis, MN 55417.
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 over-night
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 less than 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 less than 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).(ABSTRACT TRUNCATED AT 250 WORDS)
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