Cholesterol synthesis in the intestine of man: regional differences and control mechanisms

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Abstract

Cholesterol in the circulating serum pool is derived either from absorption of dietary cholesterol or from endogenous synthesis principally in the liver and gastrointestinal tract. While the control of intestinal cholesterogenesis has been elucidated in several lower animal species, no data currently are available in the case of man. In the present study using tissue specimens obtained by suction biopsy in 29 normal subjects, we have shown the rate of cholesterogenesis is low in the stomach (25 ±6 mμmoles/g per 2 hr) and rectum (40 ±8 mμmoles/g per 2 hr); in the small bowel the rate progressively decreases in the proximal duodenum (90 ±16 mμmoles/g per 2 hr); distal duodenum (80 ±11 mμmoles/g per 2 hr); and distal jejunum (35 ±5 mμmoles/g per 2 hr); but abruptly increases in the distal ileum (280 ±33 mμmoles/g per 2 hr). Indirect evidence is provided that the intestinal crypt epithelium is the main site of this sterol synthesis. Fasting for 48 hr suppressed the rate of cholesterogenesis in the distal duodenum from a control value of 80 ±11 mμmoles/g per 2 hr to 40 ±8 mμmoles/g per 2 hr while cholesterol feeding for 7 days did not alter the rate of cholesterol synthesis (75 ±12 mμmoles/g per 2 hr). This resistance to cholesterol feeding also was present in the distal ileum where control and cholesterol-fed subjects had comparable rates of cholesterogenesis (280 and 261 mμmoles/g per 2 hr, respectively). Interruption of the enterohepatic circulation, in contrast, resulted in greatly enhanced sterol synthesis with a mean rate of 259 ±29 mμmoles/g per 2 hr being found in the duodenum of four patients with biliary obstruction as compared with the rate of 80 ±11 mμmoles/g per 2 hr in control subjects. These studies indicate that the mechanisms of control of cholesterol synthesis by the human intestine are similar to those described for the intestine of lower animals; this also appears to be true for the human liver. Thus, the marked differences in over-all cholesterol metabolism between various lower mammalian species and man cannot be explained by fundamental differences in control mechanisms; rather, these differences must reflect variations in some other parameter of cholesterol metabolism.

Authors

John M. Dietschy, William G. Gamel