Cholesterol synthesis in the squirrel monkey: relative rates of synthesis in various tissues and mechanisms of control

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Abstract
According to current concepts, the liver and gastrointestinal tract are considered to be the major, if not the sole, sources of circulating serum cholesterol. While several mechanisms have been described which control the rate of hepatic cholesterogenesis, only biliary diversion is known to alter the rate of sterol synthesis in the intestine. The present study was designed to identify the inhibitory constituent of bile and to define its anatomic and biochemical sites of action. After either biliary diversion or cholestyramine feeding, there is a marked enhancement of cholesterogenesis at every level of the small intestine; this effect is specific for sterol synthesis since acetate incorporation into fatty acids and CO2 is unaffected by these experimental manipulations. In the present investigation bile salt has been shown to be the constituent of whole bile responsible for the inhibited rate of sterol synthesis found in the intact animal, and in addition, an inverse relationship has been shown to exist between the steady-state intraluminal bile salt concentration and the rate of cholesterogenesis in the adjacent bowel wall. The inhibitory effect of bile salt is directed at the cells of the intestinal crypt, the major anatomic site for sterol synthesis in the small bowel. This feedback inhibition has been localized in the biosynthetic sequence to a step between acetyl CoA and mevalonic acid and, presumably, is at the enzymatic step mediated by hydroxymethylglutaryl reductase. These studies emphasize the close interrelationship which exists between the mechanisms of control of cholesterogenesis in the liver and small intestine. Sterol synthesis in the liver is regulated by exogenous cholesterol intake, whereas the rate of intestinal sterol synthesis is controlled by bile salt, the major end product of the hepatic catabolism of cholesterol.