Feedback Control of Cholesterol Synthesis in Man*

Abstract

The ingenious balance studies of Schoenheimer and Breusch (1) first demonstrated that cholesterol metabolism in animals is under homeostatic control. It remained, however, for the isotopic experiments of Gould (2), Frantz, Schneider, and Hinkelman (3), and Tomkins, Sheppard, and Chaikoff (4) to prove conclusively that the feeding of cholesterol promptly suppresses hepatic cholesterol synthesis. The mechanism of this inhibition of cholesterol synthesis by dietary cholesterol has subsequently been studied extensively (5, 6) and has been shown to possess the characteristics of a negative feedback control system. Thus, in the sequence acetyl CoA ->/,8-hydroxy-f3-methylglutaryl CoA --mevalonic acid -> cholesterol, a single reaction, the reduction of 8-hydroxy-,8-methylglutaryl CoA to mevalonic acid, has been shown to be the primary site of the depression in cholesterogenesis produced by exogenous cholesterol (7,8).It has also been demonstrated that this feedback system is operative in the livers of every species of experimental animal so far examined (2, 9, 10). Although it would thus seem likely that such a homeostatic mechanism would be present in human liver as well, no evidence for its existence in man has so far been reported. Furthermore, the only previous in vitro study of cholesterol synthesis in man (11) ployed in the latter experiments and because of the physiological importance that such a feedback mechanism, if present, would have in controlling cholesterol synthesis in man, this problem seemed to warrant further study. The present investigation was therefore carried out to determine the effect of dietary cholesterol on the rates of cholesterol synthesis in liver specimens obtained by biopsy from well-fed, unanesthetized human beings. The results clearly demonstrate that under the physiological conditions employed in this study, human liver synthesizes cholesterol at rates comparable to those seen in other animal species. Furthermore, we conclude that human liver does possess a negative feedback system for the control of cholesterol synthesis and that this mechanism is at least as sensitive as that previously noted in experimental animals. METHODSThe subjects whose tissues were used in these studies were five women and eight men who were patients on the medical service of Parkland Memorial Hospital. Only patients from whom liver biopsies were to be obtained for diagnostic purposes were employed in this study, since we did not feel justified in obtaining such biopsies purely for experimental purposes. A variety of diseases had been diagnosed in these patients before biopsy (Table II), but six of the biopsy specimens were subsequently found to be histologically normal. Only patients who were in a good nutritional state and were eating the routine hospital diet were included in the study.Dietary records were kept of the food intake for 3 days before biopsy to insure that food consumption was adequate. One day's intake of the normal hospital diet was estimated to contain an average of 616 mg (range, 363 to 9...

Metabolism of adrenal cholesterol in man

“…Indeed, if one milligram of protein nitrogen corresponds to 75-100 mg of adrenal tissue (reference 18 and personal observations), our data indicate that the mean in vitro conversion of acetate-2-14C to cholesterol within the zona fasciculata is normally of the order of 5,000-3,500 pmoles/g per 3 hr. These figures are practically identical to those found by Bhattathiry and Siperstein (20) in normal hepatic tissue obtained by liver biopsy in patients submitted to a highcholesterol diet, i.e., when the human hepatic cholesterol synthesis is almost completely suppressed. On the other hand, under ACTH stimulation we find that the conversion of acetate-2-uC to adrenal cholesterol increases considerably and can even exceed 300,000 pmoles/g per 3 hr, a figure which is now practically identical to those obtained by Bhattathiry and Siperstein (20) in the liver from patients submitted to a normal cholesterol diet: indeed, under these circumstances the hepatic incorporation of acetate-l-C into cholesterol was found to average 282,000 pmoles/g per 2 hr.…”

In Vivo Demonstration of the Cholesterol Feedback System by Means of a Desmosterol Suppression Technique

“…2 C, the feeding of a high cholesterol diet to a triparanol-treated rat causes a virtually complete suppression of plasma desmosterol. 8 The commercial diets fed these rats contained 0.072%…”

“…It has, for example, been well established by isotopic methods that under in vitro conditions, cholesterol synthesis in the livers of all higher animals (4-7), including man (8), is under sensitive feedback control; however, the quantitative effect of exogenous cholesterol on cholesterol production when examined in vivo has yielded more variable results 1 (9)(10)(11)(12)(13)(14). Moreover, while it is wellknown that the intestine contributes to the plasma cholesterol pool (15,16), the quantitative importance of this source of blood cholesterol in the intact animal remains to be established firmly.…”

Studies on the influence of dietary cholesterol on cholesterol metabolism in the isotopic steady state in man.

“…First, dietary cholesterol suppresses the hepatic synthesis of cholesterol in the human (10) as well as in other species (11) via a negative feedback system. However, the suppression of hepatic synthesis cannot be the only compensatory mechanism since * Submitted for publication April 29,1965; accepted July 15, 1965. Supported by grants from the U. S. Public Health Service and the American Heart Association.…”