Hydroxymethylglutaryl-coenzyme A reductase exhibits graded distribution in normal and mevinolin-treated ileum

Because the small bowel is a site of significant cholesterol synthesis, we determined the ileal distribution of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme of the cholesterol biosynthetic pathway. Immunofluorescence microscopy on unfixed snap-frozen sections of ileum and jejunum from untreated rats or dogs showed HMG-CoA reductase in the absorptive villus epithelial cells and this appeared to be strikingly localized in their apical cytoplasm. This pattern of HMG-CoA reductase staining approximated a gradient along the villus-crypt axis with the distal villi labeling most intensely. Treatment of rats with mevinolin and/or cholestyramine for 12 days induced a 5- to 11-fold increase in ileal HMG-CoA reductase activity, and yielded a higher intensity of immunostaining without altering the pattern of enzyme distribution observed in control intestines. Also, rats with maximal induction of ileal HMG-CoA reductase exhibited a twofold increase in the number of epithelial villus cells containing prominent stacks of smooth-surfaced membranes in their apical cytoplasm as seen with electron microscopy. These observations suggest that the distal villus absorptive epithelial cells of the ileum contain high concentrations of HMG-CoA reductase, and therefore might be capable of contributing significant quantities of cholesterol to the circulation.