Abstract
The regulation of intestinal cholesterol synthesis was studied utilizing canine ileal mucosa maintained in organ culture for 6 h. Viability was monitored by light and electron microscopy, measurement of cellular enzymes, and the ability to actively transport a glucose analogue. The activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.4.3.4), the rate-limiting enzyme of cholesterol synthesis, increased 4-fold during a 6-h culture. A parallel increase occurred in the rate of acetate incorporation into digitonin-precipitable sterols during this period. This increase could be prevented by the addition of cycloheximide to the culture. Pure cholesterol, 7-ketocholesterol, and 25-hydroxycholesterol, when present during the last 4 h of culture, also caused significant suppression of the rise in HMG-CoA reductase activity (final HMG-CoA reductase with the three sterols was 77 +/- 4%, 68 +/- 5%, and 58 +/- 3% of control postculture value). Bile salts at low, nontoxic concentrations also inhibited the increase of enzyme activity (2 mM taurocholate = 63 +/- 3% of control, 0.5 mM taurochenodeoxycholate = 76 +/- 6% of control). In contrast, dog lipoproteins separated by ultracentrifugation failed to significantly affect intestinal cholesterol synthesis in these short term organ cultures.
Highlights
The regulation of intestinal cholesterol synthesis was studied utilizing canine ileal mucosa maintained in organ culture for 6 h
Quantitative interpretation is difficult since cycloheximide affects other processes and may have diminished the viability of the intestine somewhat, these results suggest that protein synthesis is required for the induction and maintenance of the increase in HMG-CoA
Reductase-Because of prior studies indicating that bile salts play an important role in the regulation of intestinal cholesterol synthesis [4], we studied their effect on HMG-CoA reductase in cultured intestine
Summary
The regulation of intestinal cholesterol synthesis was studied utilizing canine ileal mucosa maintained in organ culture for 6 h. A parallel increase occurred in the rate of acetate incorporation into digitonin-precipitable sterols during this period. This increase could be prevented by the addition of cycloheximide to the culture. Dog lipoproteins separated by ultracentrifugation failed to significantly affect intestinal cholesterol synthesis in these short term organ cultures. Intestine is the second most active site of cholesterol synthesis [1, 2] the regulation of cholesterol synthesis by this organ has been investigated in several laboratories. Gould reported that cholesterol feeding almost completely inhibited cholesterol synthesis in dog liver while the inhibition in intestinal mucosa was only about 30%
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