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The cholesterol-7α-hydroxylase activity of hepatic microsomal preparations of hypothalamic hypercholesterolemic rats and normal rats was assayed in rats fed diets high and low in cholesterol, and in rats killed at the supposed height and at the nadir of the diurnal cycle of enzyme activity. The activity of this enzyme system appeared to be unimpaired in the hypothalamic hypercholesterolemic rat.

Plasma cholesterol was observed to fall after release of biliary obstruction without any concurrent change in biliary excretion of cholesterol. Excision of the nerve trunks accompanying the hepatic artery did not change the degree of hypercholesteremia following biliary obstruction. No significant change in the cholesterol content of hepatic tissue occurred following biliary obstruction. Animals with gastro-intestinal systems removed exhibited no significant change in plasma cholesterol, whereas those subjected to gastro-intestinal removal plus biliary obstruction exhibited a marked hypercholesteremia. Anastomosis of the bile duct to the inferior vena cava resulted in a hypercholesteremia similar to that occurring after obstruction of the bile duct.

The absorption of oral cholesterol by rats was followed directly by analyses of the thoracic lymph and indirectly by calculating the deficit of fecal cholesterol under the amount fed. The two methods checked within about 20 per cent, with fecal analyses indicating the greater absorption. The absorbed cholesterol was found to be deposited in the liver, only very minor quantities being found in other organs or plasma. Bile is necessary for normal absorption of cholesterol, although very small amounts are absorbed even in its absence. Excess oral cholic acid increases the absorption of cholesterol by otherwise normal animals. The rat absorbs about 47 per cent of a single 50 mg. dose of cholesterol and about 34 per cent of a 100 mg. dose.

PITUITARY growth hormone was found to be essential in the normal regulation of the rat's serum cholesterol during a study of the cause(s) of the hypercholesterolaemia usually observed in the hypophysectomized rat.

Separation and isolation of hepatic parenchymal from reticulo-endothelial cells of rats given cholesterol-4-C14 was accomplished. Radioactivity was found in both cell types 6 and 24 hours following oral administration, indicating that the reticulo-endothelial cells play a role in the disposition of dietary derived cholesterol.

IT HAS been abundantly demonstrated that the liver rapidly metabolizes hydrocortisone (compound F) both in vivo and in vitro (1–8). Alterations are effected both in the side chain at C17 and in saturation of double bonds in ring A. Bile has been demonstrated to be an excretory pathway for metabolites of hydrocortisone, but the nature of these substances in bile has not been clearly characterized (8, 9). The work reported here represents data gathered by a study of this problem in the isolated perfused rat liver. MATERIALS AND METHODS A perfusion apparatus for the isolated rat liver was employed which has been described in detail in previous publications (10, 11). Hydrocortisone was determined in plasma by the Silber-Porter method (12). Hydrocortisone was determined in bile by the same chloroform extraction as used in dealing with plasma. When H2SO4 was added however, a cherry-red interfering substance developed in both the blank (extract plus H2SO4) and the sample (extract plus phenylhydrazine plus H2SO4)...

SummaryIntestinal lymph was collected from both normal and hypothalamus-injured rats given 3H-cholesterol or 3H-tripalmitin. It was found that chylomicronous cholesterol obtained from the hypothalamus-injured rat was removed from the blood and accumulated in the liver of the normal rat at the same rate as chylomicronous cholesterol collected from normal rats. However, the liver of the hypothalamus-lesioned rat removed normal chylomicronous cholesterol from plasma at a much slower rate than the liver of the normal rat. Chylomicronous triglyceride, however, was removed from plasma at a normal rate by the lesioned rat.The heparin-induced lipoprotein-lipase activity of the plasma of hypothalamus-injured rats was significantly greater than that of the plasma of normal rats.

SummaryAn electrolytic lesion placed in the anterior hypothalamus of rats fed 3 ml of cottonseed oil prevented the milieu-induced postprandial hyperlipemia usually observed in these animals. Thus the average 6-hr post-prandial plasma triglycerides (PTG) of the lesioned rats was 40 mg/100 ml and that of the controls was 91 mg/100 ml. A similar lesion placed in the tuberal area of the hypothalamus was not similarly effective.

Injection of triton WR-1339 into rats leads to a rapid increase in the cholesterol, cholate, and various lipid fractions of their blood. The increase in cholesterol is confined to the blood itself. The cholesteremic effect of triton was not dependent upon a prior accumulation of cholate in plasma. The liver was found to be the source of the excess cholesterol but the rate of cholesterol synthesis, the excretion of cholate, and the cholesterol content of the liver were not changed by injection of triton. The cholesteremic effect of triton is not due to alteration in the intestinal excretion of cholesterol. Transfer of blood between "tritonized" and normal rats leads to a disappearance of the hypercholesteremia in the former and its appearance in the latter animals. The plasma proteins of rats injected with triton are markedly changed qualitatively. Heparin was found to inhibit the hypercholesteremic effect of triton. The hypercholesteremia following triton injection appears to be due to a fundamental physicochemical change in the plasma proteins produced by injection of this detergent.

DESPITE the profound influence of thyroid activity upon cholesterol metabolism (Rosenman, Friedman and Byers, 1951, 1952; Friedman, Byers and Rosenman, 1952; Byers, Friedman, and Rosenman, in press), there is little evidence that similar influence is exerted by other endocrine glands. More recently, however, changes in serum cholesterol have been described following administration of adrenocorticotrophic and adrenocortical hormones (Conn, Vogel, Louis and Fajans, 1950; Adlersberg, SchaefTer and Drachman, 1950). It therefore was believed important to determine whether these and other hormones altered hepatic synthesis of cholesterol. Previous studies from this laboratory clearly have shown that the liver is the main source of the plasma cholesterol content (Friedman, Byers and Michaelis, 1951), and that the biliary concentration of cholesterol is a reliable index of the rate of hepatic synthesis of this substance (Byers and Friedman, 1952). Therefore, it is believed that studies of the effects of various s...

The rate of cholesterol synthesis, measured by the rate of incorporation of tritium from body water into the cholesterol molecule, was found to be greater than normal in the hyperthyroid rat and below normal in the hypo-thyroid rat.

The rate of disappearance of intravenously injected triolein I131 from the blood stream and its concentration in various tissues were studied both in the normal and in the atherosclerotic rabbit. No difference in the rate of disappearance of the I131 from blood was observed between the normal and atherosclerotic rabbit. The atherosclerotic aorta was observed to take up approximately twice as much I131 as normal aorta when the tissues were assayed 10 minutes after injection. However, 24 hours after injection no essential difference was observed. All other tissues examined (fat, adrenal, spleen and liver) were observed to take up and retain more I131 than either the normal or the atherosclerotic aorta. The results suggest that the atherosclerotic aorta of the rabbit, while taking up initially more I131 than the normal aorta, appears to metabolize or otherwise rid itself of such I131 as rapidly as the latter in a period of 24 hours.

SummaryHeparin administration decreases the hyperlipemia and hypercholesteremia of rats with established nephrosis, induced by injection of rabbit antirat kidney serum. Heparinization during the induction phase of the nephrotic state appears to suppress or prevent ascites and edema, and to reduce markedly the degree of lipemia, hypercholesteremia and lipemic-turbidity of the plasma. Possible mechanisms of this arresting effect of heparin are discussed briefly and it is suggested that heparin suppresses the causal mechanism whereby nephrosis is induced in rats by injection of anti-kidney serum.

SummaryHeparin-activated lipolytic mechanisms were studied in vitro in rats with nephrosis experimentally induced by injection of antikidney serum. The nephrotic rat was found normally capable of releasing lipoprotein lipase following heparin administration. The nephrotic rat's plasma also was found normally capable of supporting lipoprotein lipase-induced hydrolysis of a triglyceride substrate.

Thoracic duct lymph was collected from groups of rats fed varying doses of β-sitosterol concomitantly with cholesterol. The results indicated that β-sitosterol exerts only a slightly inhibiting effect upon intestinal absorption of cholesterol in the rat.

SummaryGruel obtained from experimental thromboatherosclerotic plaques and from human coronary artery plaques was tested in in vitro studies for its possible thromboplastic potency. Gruel from experimental thromboatherosclerotic plaques was moderately thrombogenic, but that obtained from the human plaque appeared to be non-thrombogenic. The lipid extract of the experimental gruel failed to exhibit any thrombogenic propensity.

Simultaneous feeding of dihydrocholesterol and cholesterol to rats significantly reduced the amount of cholesterol absorbed into the thoracic lymph. Hypercholesteremia and hyperphospholipemia developed in rats simultaneously fed cholesterol and cholic acid for 8 weeks. The addition of dihydrocholesterol to this diet also decreased the rate of development and magnitude of the hypercholesteremia, but had no apparent effect upon the rise of plasma phospholipids.

The action of triton WR-1339 in retarding the escape of triglyceride fat from plasma, formerly established in the rat, was confirmed in the rabbit. The atherosclerotic rabbit responds to the fat-retaining action of triton nearly as effectively as does the normal animal. The preferential concentration of I131 from triolein in the aortic atherosclerotic infiltration, as compared with normal aorta, was enhanced and prolonged by the use of triton.

Summary1. Normal rabbits were able to rid their plasma of excess cholesterol just as rapidly after such cholesterol was administered in the form of rabbit hypercholesteremic serum, as when administered in the form of rat hypercholesteremic serum. 2. Hypercholesteremic rabbits whose plasma level of cholesterol was reduced by exchange transfusions exhibited a return to higher levels in succeeding days. 3. Normocholesteremic rabbits whose level of cholesterol was elevated by exchange transfusions quickly reverted to their previous normocholesteremic status. 4. These facts suggest that the chronic discharge of previously stored tissue cholesterol is responsible for the long persistent hypercholesteremia in the rabbit after cessation of cholesterol feeding.

Quantitative studies regarding the fate of parenterally injected digitoxin in the rat were made by assaying extracts of rat tissue by the embryonic duck heart method. The concentration of digitoxin found in heart muscle was similar to that found in lung and kidney and greater than the concentration in skeletal muscle. The greatest amount was found in the liver and suggested the importance of this organ in the excretion or destruction of digitoxin.

SummaryIntermittent intravenous infusion of a phosphatide emulsion into 2 series of previously hypercholesteremic rabbits appeared to effect a marked resolution of their atherosclerotic infiltratio...

Eleven substances capable of either augmenting or depleting the alpha- and - beta-adrenergic capacities of the autonomic nervous system were administered to rats exhibiting hypothalamic hypercholesterolemia and to normal controls. Only the beta-adrenergic blocking agents propranolol and possibly 6-OH dopamine were observed to alter (raise) the serum cholesterol concentration, and this occurred in both experimental and control animals. Neither atropine, nor the serotonin-depleting agent, rho-chlorophenylalanine, nor the serotonin-antagonist cyproheptadine, were observed to alter serum cholesterol level. Such absence of effect was also noted with metaraminol, phenoxybenzamine, isoproterenol, epinephrine, reserpine, and alpha-methyl tyrosine.

SummarySome of the possible mechanisms responsible for the hypocholesterol-emic effect of glucagon were investigated. Glucagon was found to inhibit the intestinal absorption of cholesterol. In addition, it was found to either hasten the rate of egress of lipoprotein cholesterol from the blood into the liver or to retard the rate of re-entry of cholesterol from the liver into the blood. The data do not distinguish between these two possibilities, which indeed may occur simultaneously.

The administration of phenobarbital was observed to inhibit the rise in serum cholesterol that occurred in rats after thyroidectomy or hypophysectomy and in rabbits after inclusion of cholesterol in their diet. This hypocholesterolemic effect of phenobarbital was found to be due to its capacity to inhibit the intestinal absorption of cholesterol in both these species. We found no evidence to suggest that phenobarbital altered the endogenous process of cholesterol metabolism in either of these two species of animals.

Digitoxin administered to the rat, rabbit, or dog has no specific avidity for heart muscle. The quantity recovered from this organ at any time was no greater than from liver or kidney, while these organs continued to contain the glycoside for a much longer period of time.

The administration of thiouracil induced a rise and administration of thyroid substance a decrease of the plasma cholesterol concentration in rats. The concentration and daily output of bile cholesterol was markedly reduced in hypothyroid rats and markedly increased in hyperthyroid rats. Evidence is presented which suggests that the rate of synthesis of cholesterol is significantly increased in the hyperthyroid rat and decreased in the hypothyroid rat.

The possible role of the hepatic reticuloendothelial system in the synthesis as well as the disposition of endogenously produced cholesterol was studied in the rat by various means. Our results suggest that this system does not synthesize significant quantities of cholesterol nor participate in the egress of endogenously produced cholesterol from the plasma into the liver. It does however, play an important, perhaps indispensable, role in ridding blood of cholesterol derived from the diet.

Detailed procedure for cannulation of the hepatic lymph duct and collection of hepatic lymph from rats is described. The average rate of flow of hepatic lymph from 12 rats so cannulated was 1.5 ml in 12 hours. The maximal pressure in four rats was sufficient to raise a column of lymph to a height of 26 cm. The albumin and globulin concentration of the hepatic lymph of six rats varied inversely with the volume collected and averaged two-thirds that of the serum, although qualitatively almost identical in electrophoretic studies. The glucose content of hepatic lymph was slightly higher than that of plasma (21 rats), while cholesterol content was less than that of plasma (28 rats). The urea and cholic acid concentrations were the same in plasma and hepatic lymph, within the limits of accuracy of the used (4 and 6 rats, respectively). Following biliary obstruction in six rats, the hepatic lymph contained increased amounts of cholic acid and bilirubin and was increased in volume to an average of 5.1 ml.

SummaryExperimental hyperlipemia was produced by intravenous injection of sodium cholate into normal fasting rats. The lipemia resulted from a comparable percentage increase in the concentration of each plasma lipid fractoin, and not from preferential increase of any one particular plasma lipid.

SummaryInterference with the reticuloendothelial system by injection of India Ink was found to interfere with the ability of the rat, rabbit and dog to clear their plasma after the ingestion of cholesterol dissolved in olive oil. This interference extended not only to cholesterol, but also to total lipid and chylomicra. These findings suggest that the reticuloendothelial system plays an essential role in the disposition of exogenously derived cholesterol. The possible mechanism involved is discussed.