Effect of Endogenous and Exogenous Cholesterol on the Feedback Control of Cholesterol Synthesis*

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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...

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Feedback Control of Cholesterol Synthesis in Man*

Bhattathiry¹,

Siperstein²

1963

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“…It has long been known that plasma cholesterol does not constitute a single entity; it is variably distributed among different lipoproteins, in free and esterified forms, whether of endogenous or exogenous origin, all of which may have different functions (32). One may wonder how the adrenal tissue makes the distinction among the many circulating forms of cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Blood Cholesterol and Hydrocortisone Production in Man: Quantitative Aspects of the Utilization of Circulating Cholesterol by the Adrenals at Rest and under Adrenocorticotropin Stimulation*

Borkowski¹,

Levin²,

Delcroix³

et al. 1967

Summary. A kinetic study of the conversion of blood cholesterol into hydrocortisone was carried out in two patients through prolonged infusions of cholesterol-4-14C. The following points appear to be established by our observations:1) The infused tracer behaved metabolically like endogenous cholesterol; it could therefore serve as a means of labeling plasma cholesterol for investigating its utilization by the adrenal cortex.2) At rest, about 80% of hydrocortisone derived from plasma cholesterol, the other 20% thus being synthesized in situ from acetate and other unlabeled precursors.3) Under ACTH stimulation the participation of plasma cholesterol in the synthesis of hydrocortisone was the same as at rest; the conversion of plasma cholesterol into hydrocortisone was thus proportional to the production of glucocorticosteroids by the adrenal glands.4) The specific activities of hydrocortisone allowed us to trace its adrenal precursors including adrenal cholesterol. The kinetics of the replacement of adrenal cholesterol by plasma cholesterol underlined the functional heterogeneity of the former. The experimental data were compatible with the following model: A fraction of plasma cholesterol entering the adrenal cell is immediately available for metabolism and conversion into steroid hormones, and another fraction turns over slowly, representing some form of storage.

“…It should be noted that an identical observation has been made previously by McGarry and Foster (20). We have previously reported that exogenous cholesterol represents a far more effective inhibitor of hepatic cholesterol synthesis than is endogenous cholesterol (19); however, over long periods of time high levels of endogenous cholesterol, probably through enterohepatic circulation, lead to a severe inhibition of hepatic cholesterol synthesis. It is likely that through this mechanism the sterols produced over many months by tumors can cause the direct inhibition of hepatic cholesterol synthesis observed in the present experiments.…”

Section: As Demonstrated Inmentioning

confidence: 98%

Loss of the Cholesterol Feedback System in the Intact Hepatoma-Bearing Rat

Bricker¹,

Morris²,

Siperstein³

1972

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A B S T R A C T By means of the desmosterol suppression technique described in the previous paper, the influence of hepatomas on sterol metabolism has been studied in the intact rat. The major finding of this study is that all hepatoma-bearing rats demonstrate a consistent in vivo loss of the cholesterol feedback system that is characteristic of normal liver. The results also demonstrate that such tumors retain only minor amounts of the sterol they synthesize, releasing over 90% of such endogenous sterol into the circulation. Finally, the in vivo loss of cholesterol feedback control was found to occur in at least two minimal deviation hepatomas and in one highly malignant adenocarcinoma of hepatic origin. These