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Six hypercholesterolemic and five normocholesterolemic subjects were injected twice daily with human growth hormone for 7 days. During HGH administration, the average serum cholesterol of both types of subjects fell significantly, and their serum triglyceride levels increased. Peak insulin responses to glucose also increased. However, no change occurred in the serum phospholipid, FFA, cortisol, or thyroxine concentrations during HGH treatment.

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.

By employing the embryonic duck heart method to assay digitoxin quantitatively in extracts of human urine, it was found that, contrary to previous opinion, a large percentage of ingested or in-injected digitoxin is excreted via the kidney in a physiologically active state. Approximately 40 per cent of a digitalizing dose (1.2 mg.) is excreted over a period of 12 to 24 days. The average rate of renal excretion in theoretically digitalized normal young individuals was found to vary from 30 to 50 µg. of digitoxin per day, while those showing signs or symptoms of overdosage excreted significantly greater amounts of digitoxin.

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.

Cortisone, 5 mg/day, first increased the plasma triglyceride levels of 2.5-kg male rabbits fed stock, high-fat, fat-free, or semistarvation diets. Later, hypercholesteremia was observed only in those plasmas in which triglyceride levels exceeded 400 mg/ml. Cortisone diminished accumulation of stainable fat in livers of animals fed fat, and of carbon particles in Kupffer cells; it caused parenchymal cells to enlarge and show vacuolization, abnormal nuclei, and fragmented cell walls. Rate of loss from plasma of parenterally administered triglyceride was similar in cortisone-treated and hepatectomized rabbits. Cortisone did not alter: lipid absorption, liver cholesterol, incorporation of acetate into cholesterol, bile cholesterol, rate of exit of cholesterol from plasma, Triton-induced hyperlipemia, or lipoprotein-lipase. Concentration of liver glycogen did not correlate with cortisone-induced lipemia. The authors suggest that cortisone induces hypercholesteremia only indirectly as a result of a sufficient degree of preceding hypertriglyceridemia, which stems in part from a relative inability of the liver to remove triglyceride from plasma.

I. INTRODUCTION ALTHOUGH it is almost thirty years since abnormalities of blood cholesterol content were observed to follow deranged thyroid activity (1), the mechanism responsible for these changes remains unknown. Moreover, the obscurity surrounding this interesting thyroid-blood cholesterol relationship has persisted, despite the clinical recognition (2) of a possible association between the hypercholesteremia of the hypothyroid state and the premature atherosclerosis believed by many to occur in this disease. It appeared important to investigate some of the underlying processes concerned with the altered blood cholesterol level in both the hyperthyroid and hypothyroid states. By using various new techniques we have been able to discover that the underlying fault in cholesterol metabolism in the hyperthyroid state is one in which an increase occurs, not only in the rate of manufacture, but also in the rate of excretion and destruction of cholesterol. We have also found that, conversely, the same proces...

Elevation of plasma cholate (by intravenous injection of sodium cholate) in both the normal rat and the rat with biliary obstruction was found to lead to an elevation of plasma phospholipid and cholesterol. Experimental elevation of plasma phospholipid (also by injection), however, while leading to an elevation of plasma cholesterol did not elevate the plasma cholate in either the normal or obstructed rat. Furthermore, comparison of the cholesterol-phospholipid ratio obtained in rats by infusion of phosphatide with those observed in rats with biliary obstruction suggests that the plasma phospholipid elevation occurring spontaneously in these latter rats induced the hypercholesteremia observed. In view of these observations, it is suggested the elevation of plasma bile acid occurring in biliary obstruction effects its hypercholesteremic effect by first leading to the elevation of plasma phospholipid. The latter in turn leads to the hypercholesteremia observed.

Rabbits fed cholesterol- and oil-supplemented diet were carefully paired for equality of plasma cholesterol concentration during the feeding period and a subsequent 30 days of normal diet. The normal diet was continued and one of each pair of rabbits was then subjected to intravenous infusion of mixed phosphatides of animal or soybean origin twice weekly for an average of 11 infusions. At the end of this time the aortas of the infused rabbits showed markedly less atherosclerosis than their paired controls, both grossly and when assessed on the basis of cholesterol content. When implants of atherosclerotic aorta were made into the anterior chamber of the eyes of normal host rabbits, infusions of phosphatide did not accelerate the decline in cholesterol content of the implants or affect the normal cholesterol content of the host rabbit's own aorta. When normal rabbit aorta was implanted into normal host rabbits thereafter fed a diet enriched in cholesterol and oil, infusion of phosphatide had no effect on atherosclerosis of the host's own aorta. However, a marked increase was observed in sudanophilia and cholesterol content of the aortic implants in those rabbits receiving infusions. Apparently the lipid dynamics of ocular aortic implants differs from that of the aorta in situ. Infusions of phosphatide can alleviate atherosclerosis when a cholesterol-free dietary is followed but may worsen atherosclerosis when a cholesterol-free diet is not followed.

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.

A method is described for determining net changes in glycogen content of the isolated rat liver after 6 hours of perfusion using the glycogen content of the caudate lobe of the liver as a control value. A series of experiments was performed in which livers obtained from normal and hyperthyroid rats were perfused at low and high perfusate glucose levels and the glycogen content of the livers was determined before and after perfusion. It was found that the isolated liver from the untreated rat under artificial perfusion neither increases nor decreases appreciably in glycogen concentration during a period of six hours at either low or high glucose perfusate concentrations. In contrast, the isolated hyperthyroid rat liver, which is uniformly low in glycogen concentration, effects a marked increase in its glycogen concentration by the end of perfusion at high perfusate glucose concentration (above 600 mg.%). It was concluded that the data confirm the effect of thyroxine in depleting the liver of its glycogen content, and establishes that thyroxine-influences the metabolism of the hyperthyroid liver and its enzyme systems in promoting glycogen storage even in the presence of increased glucose metabolism.

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)...

A 20-cm length of Ir192 wire was placed for 48 hours in the proximal portion of the aortas of a series of rabbits. The rabbits, when subsequently fed a diet containing excess cholesterol, failed to exhibit significant atherosclerosis, as compared to the control animals, in that pontion of the aorta which received the irradiation. The histological and chemical studies performed upon these rabbits suggest that the antiatherogenic effect of the irradiation was due primarily to the suppression of the intimal hyperplastic response to a persistent hypercholesteremia usually observed in the rabbit's aorta.

Administration of either a lyophilized or gel preparation of corticotropin in sufficient amounts is capable of lowering the fasting and postprandial elevation of the plasma triglyceride of the hyperlipemic as well as the normolipemic subject, regardless of whether the subject exhibits a behavior pattern of the A or B type. This hypolipemic effect of the corticotropin preparation was not found to be due to its possible lipotropin or growth hormone content. On the basis of these results, it is concluded that corticotropin can serve as a hypolipemic agent in man. The administration of a specially prepared and essentially pure corticotropin replicated the hypolipemic effects of the commercial preparation of ACTH. Administration also of either hydrocortisone or epinephrine failed to effect the hypolipemic influence observed after injection of corticotropin.

The fecal output of cholesterol and of noncholesterol sterols was determined in hyper- and hypo-thyroid rats, and in a group of control animals. The intestinal excretion of cholesterol and of total digitonin-precipitable sterols was found to be considerably increased in the hyperthyroid, and considerably decreased in the hypothyroid animals. The relationship of these findings to the altered plasmal cholesterol content occurring in deranged thyroid states is discussed.

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.

SummaryChanges in the rat plasma concentration of cholesterol were effected by lecithin infusion, biliary obstruction, clofibrate administration, and by induction of hypothyroidism. The extent of incorporation of 32P into hepatic phospholipid was altered (i.e., decreased) in only those rats subjected to lecithin infusion. However, changes in the plasma content of labeled phospholipid were observed only in those animals subjected to biliary obstruction (increase) or clofibrate (decrease) administration.

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.

SummaryThe plasma corticotropin and cortisol concentrations of 9 coronary-prone (Type A behavior pattern) and 10 coronary-resistant (Type B behavior pattern) subjects were studied at 6 time intervals during their waking hours. The average plasma corticotropin content of the 9 Type A subjects was significantly greater during the total period measured than that of the 10 Type B subjects. The average daily peak value of plasma corticotropin of the Type A subjects also was found to be significantly increased. No significant differences were found in either the average or peak plasma cortisol values between these 2 groups of subjects.The authors express their thanks to Drs. Berson and Yalow for their ACTH analyses of the plasma samples of these subjects.

The renal excretion of digitoxin was studied in cardiac patients who were (1) decompensated and (2) compensated. It was found that the renal excretion of digitoxin was not changed in patients suffering from left ventricular failure alone but diminished considerably during the first 24 hours of decompensation in patients suffering from both right and left ventricular failure. Patients who were maintained in a good state of compensation by adequate digitalization were found to excrete 30 to 40 per cent of their daily dose of digitoxin. Patients overdigitalized were found to excrete 70 or more micrograms of digitoxin a day. The maximal amount of digitoxin able to be destroyed in the body was considered to be approximately 50 µg. per day, a finding which explains why dosages in excess of 0.15 mg. almost invariably lead to overdigitalization.

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 induction of a continuous state of hyperphospholipidemia in rats by the infusion of an emulsion of commercially pure soybean phosphatides quickly led to a rise in the plasma cholesterol of the animals. The degree of this rise moreover appeared to be directly dependent upon either the amount of phosphatides injected or the rise in plasma phospholipid occasioned by the injected phosphatides. The hypercholesteremia induced in this fashion was not affected by diversion of the animal's own intestinally derived cholesterol. A similar but less constantly induced hypercholesteremia also was observed to occur soon after the continuous injection of either a saturated or unsaturated type of neutral fat. Although such injection of fat also led to a rise in plasma phospholipid, this latter rise did not appear to be totally responsible for the hypercholesteremia induced. The results suggest not only that hypercholesteremia may be induced by experimental elevation of either plasma phospholipid or neutral fat but also that the hyperlipemia observed in various hypercholesteremic states may be involved in the latter's pathogenesis.

Summary1. Administration of highly unsaturated fats to the rat effected a greater intestinal absorption of cholesterol than similar administration of saturated fats. 2. Following continued ingestion of highly unsaturated fat, there was evidence that the fall in plasma cholesterol observed was accompanied by a marked increase in excretion of both cholesterol and bile acid in the bile. 3. The possible relationship of reduction in plasma cholesterol to the observed change in bile cholesterol and bile acid excretion is discussed.

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.

Twelve phosphatide preparations from vegetable, animal, yeast and synthetic sources were infused intravenously into normal or functionally hepatectomized rats at such a rate as to maintain plasma phospholipids at 2–10 times normal levels over a period of 6–24 hours. Consequent upon such infusion, plasma cholesterol concentration rose significantly. All preparations were active in greater or lesser degree, with the exception of duck egg lecithin.

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.

SummaryThe intake of simple sugars of 6 moderately hypertriglyceridemic, hypercholesterolemic subjects was reduced for 60 days. This restriction led to a moderate weight loss, a normalization of their previously elevated pre-beta lipoprotein levels and a moderate decrease in their pre- and postprandial hypertriglyceridemia. The elevated serum cholesterol and pre- and postprandial serum insulin levels were not normalized by the dietary change.

To investigate the tissue source of the excess cholesterol appearing in plasma during phosphatide infusion, various tissues of the rat were analyzed for their cholesterol content during phosphatide induced hypercholesteremia. In rats prefed a sterol-free diet, phosphatide-induced hypercholesteremia did not lead to any discernible change in the cholesterol content of any organ or tissue analyzed except liver and adrenal. The cholesterol content of the liver was increased and that of the adrenal, decreased at the height of the induced hypercholesteremia. In rats prefed excess cholesterol, a decline in liver as well as adrenal cholesterol occurred with no discernible change in any other tissue studied. It was postulated that induced hyperphospholipidemia appears capable of mobilizing only stored or excess cholesterol from any tissue.

1. 1. Tritium-labeled cholic acid was prepared by biosynthesis in the rat. 2. 2. The administration of tritium-labeled cholic acid to the bile duct obstructed rat followed by examination of the body cholesterol for activity gave no evidence of conversion of cholic acid to cholesterol. 3. 3. The conversion of cholesterol to cholic acid has been confirmed in the rat. 4. 4. The mechanism by which excess cholic acid produces excess hypercholesteremia in rats with biliary obstruction does not involve conversion of cholic acid to cholesterol.