THE METABOLISM of CHOLESTEROL by B

Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from 208

THE METABOLISM OF CHOLESTEROL By B. LEWIS, PH.D., M.D.(Cape Town) Formerly Research Officer, Clinical Nutrition Research Unit, Department of Medicine, University of Cape Town C. J. Adams Travelling Fellozv for 1959

The biochemistry of the steroids is of unique interest; no other group of relatively simple substances plays so versatile a role in biology. On the one hand are many highly potent steroids occurring in minute quantities and often with HO JAJ HO H clearly-defined functions, e.g. sex hormones, CHOLESTEROL COPROSTEROL corticosteroids, the vitamins D and the cardiac glycosides. In sharp contrast are certain sterols, exemplified in the animal kingdomby cholesterol- HO OOH ,o , L familiar, abundant, readily determined, yet singu- larly obscure in their physiological significance. The structural formulae of some important HOOH HO steroids are shown in Fig. i. CHOLIC ACID VITAMIN D2

H&OH 0 qH1OH copyright. Functions of Cholesterol OOH CA In some restricted fields the functions of cholesterol are at least partly recognized. It is important in the biosynthesis of several steroid hormones (Heard et al., I956; Hechter and Pincus, 1954; CORTISOL ALDOOSTERONE Roberts and Szego, I955), and is present in high concentration in the adrenal cortex and corpus O OH luteum; it is from acetate in readily synthesized o1- OW these organs. Cholesterol is a precursor of http://pmj.bmj.com/ the corticosteroids, androgens and progesterone. HOCH ACTH causes rapid depletion of adrenocortical OESTRAD1IL TESTOSTERONE cholesterol; perfusion studies have shown that one action of this hormone is to accelerate the OH, conversion of cholesterol to 2I-carbon atom in- termediaries in corticosteroid synthesis, e.g. A5 pregnenolone (Stone and Hechter, 1954), and to the androgens. However, cholesterol is not an on October 1, 2021 by guest. Protected C,,OjC4 METHYL obligatory intermediary in the formation of DIGOXIN CHOLANTHRENE steroid hormones: some preparations of adreno- FIG. I.-Structural formulae of some steroids of cortical tissue convert labelled acetate to such biological significance. hormones without the appearance of labelled cholesterol (Heard et al., 1956; Stone and other tissues (Rosenberg, I945); this sterol is Hechter, 1954, Ungar and Dorfman, 1953). Nor thought to be derived from cholesterol, and gives are the oestrogens synthesized from cholesterol rise to the active vitamin under the influence of (Heard and O'Donnell, 1954), acetate is utilized ultra-violet light. Cholesterol esters, together in the formation of these aromatic, i.e. benzene- with sphingomyelin, form a major constituent of containing compounds, but cholesterol is not an the myelin sheaths of nerve fibres, where these intermediary. lipids may have an insulating function necessary Other probable functions of cholesterol include at least for saltatory conduction. Cholesterol the synthesis of vitamin D3. The skin contains a plays an important role in the synthesis of the bile higher proportion of 7-dehydrocholesterol than acids. The small amount of cholesterol present in Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from

April 1959 LEWIS: The Metabolism of Cholesterol 2zo all animal cells is of unknown significance; the to its combination with ai- and pi-globulins in cholesterol and phosphatide content of rat skeletal the a- and 5-lipoproteins. These complex pro- muscle is increased by exercise (Bloor, 1940), teins also contain phosphatide, some triglyceride, suggesting that in this site, too, the sterol may be and water of hydration. The protein lipid linkage of functional importance. is poorly understood; its partial cleavage by freez- ing (McFarlane, 1942) suggests that water (40 per The Plasma Cholesterol cent. by weight of p-lipoprotein) plays a part The past decade has seen a spate of investiga- (Oncley et al., 1950), but another interpretation is tions into the physiology of the circulating choles- that a ' shell' of water surrounds the lipoprotein terol and its likely relationship to atherosclerosis; molecule. Secondly, cholesterol can be removed but the interpretation of changes in plasma level from lipoprotein by certain extraction procedures, (both total and fractionated) is still more often leaving the phosphatide still bound to globulin speculative than factual. The plasma cholesterol (Lovern, 1954); the converse has not been re- arises largely by endogenous synthesis, but dietary ported. It would appear that cholesterol is to cholesterol contributes a varying proportion. The some extent a 'passenger,' attached relatively cholesterol of plasma exchanges with most tissues, loosely to the more stable (and more water-soluble) at widely differing rates, both in man and in ex- protein-phosphatide complex. Hence, a high- perimental animals (Gould, 1954; Eckles et al., serum cholesterol/phosphatide ratio, which is I955). One determinant of the rate of exchange often observed in patients with atherosclerosis of cholesterol between plasma and cells is the (Morrison, I952), may conceivably be associated availability of the specific cholesterol-binding pro- with diminished ' stability' of the lipoprotein teins et al., solution. (Eckles I955). The o-lipoprotein contains some 39 per cent. What is the physiological role of the cholesterol by weight of lipid (Oncley et al., 1950; Oncley in the blood? There is no cogent evidence for the et textbook statement that it plays a part in fatty acid al., 1949); its concentration is relatively con- stant in health and disease. On the other hand, copyright. transport; against this hypothesis is the fact that p-lipoprotein contains about 77 per cent. of the fatty acids of plasma cholesterol esters differ lipid, and is much more variable in amount. It considerably from those of depot and liver fat. comprises several components of different densi- About two-thirds of the plasma cholesterol (the ties as measured by ultracentrifugation; those of ester fraction), is combined with fatty acids. These lowest density are important in triglyceride trans- include a large proportion of highly unsaturated In some of liver acids, the mean iodine value in man being I60 port. types disease, qualitative (Bloor et al., 1938). Linoleic and arachidonic abnormalities in serum lipoproteins have been acids have two and four double bonds reported, low protein content being a feature (which (Russ et al., I956). The other category of circulat- http://pmj.bmj.com/ respectively) are prominent in plasma cholesterol ing lipid is the chylomicron fraction, visible esters (Kelsey and Longenecker, I941; Lewis, particles containing a preponderance oftriglyceride I958a); on the other hand, the fats of adipose and and little protein (OC2-globulin); these extremely liver tissue contain mainly palmitic and stearic low-density lipoproteins appear during the absorp- acids, with no double bonds, and oleic acid which tion of ingested fat, render the plasma lactescent, has one. and are removed by the complex' clearing system' Cholesterol is rapidly synthesized in the liver, and (Andersson Fawcett, 1950; Anfinsen, 1954; on October 1, 2021 by guest. Protected which organ is the main source of the plasma Bergstrom and Borgstr6m, 1956; Friedman et al., cholesterol (Friedman et al., I95i) as well as the 1956). site ofits esterification (Friedman and Byers, 1955). The relevance of this system to cholesterol But its synthesis is accomplished (at various rates) metabolism is not yet clear. It has been invoked by every tissue which has been tested except to explain the hyperlipaemia and hypercholes- mature nervous tissue; even the arterial wall can terolaemia of the nephrotic syndrome. Rosenman incorporate acetate into cholesterol (Werthessen et al.. (I957) have shown that in experimental et al., I954). The brain synthesizes cholesterol nephrosis in rats the fall in serum albumen is only until myelination is complete (Srere et al., followed by a rapid rise in serum triglyceride and 1950). Its presence in the blood does not neces- a slower elevation of cholesterol and phosphatide sarily indicate transport from a site of synthesis to levels. In view of the importance of the plasma one of utilization. albumen in transporting the fatty acids released from chylomicrons by the clearing process, it was Cholesterol Transport suggested that the changes in plasma lipids are Cholesterol is only minutely soluble in water, primarily due to hypo-albumenaemia causing a and its presence as a clear solution in plasma is due bottleneck in lipaemia clearance. Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from

o POSTGRADUATE MEDICAL JOURNAL April 1959

Synthesis, Catabolism and Excretion of FAT CARBOHYDRATE Cholesterol / .ACETO-ACETIC ACID As has been stated, most animal and human OXIDATION -ACETYL COENZYME A tissues which have been studied, can synthesize nAMINO-ACIDS" cholesterol (Friedman et al., 1955; Werthessen et al., i954). In liver homogenates labelled acetate BRANCHED- CHAIN ACIDS has been incorporated into cholesterol within o minutes (Schwenk et al., I955). The intra- CHOLESTEROL cellular site of cholesterol synthesis has been SYNTHESIS investigated by ultracentrifugation of liver homogenates; both the soluble fraction and the large microsomes appear to be necessary (Bucher and McCarrahan, I955). CATABOLISM The stages in the biosynthesis of cholesterol Cells PLASMA \ BIL ACIDS have largely been identified. Cornforth and Popjak (I958), Friedman and Byers (I956) and Bloch (195i) have provided valuable reviews of CHOLESTEROL this topic. Acetate, in its metabolically-active form acetyl coenzyme A may be regarded as the starting point, itself arising from carbohydrate, fat and protein catabolism (Fig. 2). Two molecules condense to form aceto-acetyl coenzyme A; ABSORPTIO XC RETION this substance is important as the end-product of Small Intestine '_ ELIMINATION p-oxidation of fatty acids. Condensation with a IN FAECES third molecule of acetate yields the first of a series FIG. 2.-Variables influencing the serum-cholesterol :level. of branched-chain acids including the 5-carbon copyright. atom p, P-dimethyl acrylic acid. These branched- chain acids may also be derived from amino- 20 to 33 per cent. of the serum cholesterol in rats acids (Coon, 1955). The 6-carbon atom mevalonic to be of dietary origin when the cholesterol intake acid is an important intermediary (Tavormina et was low; the percentage rose to 74 to 90 per cent. al., 1956); it is probable that (after losing one when large quantities of cholesterol were fed. carbon atom), six of the resulting molecules con- Gould et al. (I953) observed that cholesterol feed- dense to form the hydrocarbon squalene (30 carbon ing depressed the synthesis of this sterol; the lack atoms) (Cornforth et al., I958). Cyclization (the of effect of dietary cholesterol on the serum level formation of' cross-linkages ') converts this linear in man may therefore be due to a homeostatic http://pmj.bmj.com/ molecule into a condensed ring system; there is diminution of endogenous synthesis. good evidence that lanastadienol is directly formed The main end-products of cholesterol meta- in this process. Loss of three carbon atoms and re- bolism are the bile acids (Bloch et al., I943; arrangement of the ring structure subsequently Bergstr6m, I952), largely glycocholic acid in man yields cholesterol. (Siperstein and Murray, 1955). After administra- Many experiments have been published which tion of 14C-labelled cholesterol, excretion of radio- deal with factors the rate of of takes almost in the

affecting synthesis activity place exclusively faeces; on October 1, 2021 by guest. Protected cholesterol. Friedman et al. (1956) has analysed a trace appears in the urine (perhaps as steroid the difficulties in the tracer techniques involved. hormone metabolites). Only the terminal three About 70 per cent. of ingested cholesterol is carbon atoms of the cholesterol side chain are absorbed (Karvinen et al., I957). It is trans- excreted as carbon dioxide. Siperstein and ported in the lacteals (Biggs et al., I951) and Murray (I955) administered cholesterol-4-'4C appears in the plasma as low-density chylomicra intravenously to a man with a bile fistula; 98 per containing phosphatide and trighyceride but very cent. of the radio-activity appeared in the bile, little protein (Robinson, I955; Page et al., I953). and only 1.3 per cent. in the acholic faeces. Over These chylomicra are rapidly deposited in the 8o per cent. of the radio-activity in faeces is in the liver, at least in the rat (Byers et al., 1953); phago- acid fraction, probably in the form of ketonic bile cytosis by hepatic reticulo-endothelial cells may acids arising from bacterial oxidation of cholic contribute to this (Feigenbaum et al., 1954). acid in the colon. Cook et al. (1955) administered However, Messinger et al. (1950) and Keys cholesterol to rats and showed increased faecal (I952a) found that the serum-cholesterol level excretion of organic acids, probably ketonic bile in man is virtually unaffected by the dietary acids. cholesterol intake. Morris et al. (1957) found The liver is the chief site of cholesterol cata Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from

April 959 LEWIS: The Metabolism of Cholesterol 211 bolism, and several stages in the reaction sequence Bruggen et al., I952), and the serum level tends to are known. In mouse liver cells the mitochondria fall; carbohydrate feeding increases the rate of are the organelles responsible (Fredrickson, I956). incorporation of acetate into cholesterol in liver Liver tissue is not unique in its ability to convert slices (Hill et al., 1955). Many dietary saturated cholesterol to bile acid (Kendall, I958). It is im- fats elevate the serum-cholesterol level (Keys, portant to note that it has not been proved that I952b; Bronte-Stewart et al., I956). It has been bile acids can be synthesized only from cholesterol assumed that the mechanism is one of increased (Bergstr6m and Borgstr6m, I956). cholesterol synthesis from aceto-acetate derived In man, the principal faecal sterols are choles- from p-oxidation of the fatty acids. However, terol and its saturated derivatives, coprosterol and coconut fat feeding (which regularly elevates cholestanol. Much of the cholesterol is secreted serum-cholesterol levels), does not accelerate the by the small intestine; a variable amount is incorporation of acetate into cholesterol (Wood derived from dietary cholesterol, and relatively and Migicofsky, 1958). Another possibility has little is contributed by the bile. Plant sterols are been raised by Hellman et al. (I957) who fed only slightly absorbed (Cook et al., I955): dietary various fats for long periods to a patient with sitosterol, for example, appears in the faeces, hypercholesterolaemia, then administered choles- largely as sitocoprosterol. terol-4-14C. They measured the faecal excretion of Cholesterol absorption takes place in the small 14C, and ascribed the rising serum-cholesterol levels intestine. Isolated rat intestine absorbs both free during butter-oil feeding to diminished intestinal and esterified cholesterol against a concentration excretion of cholesterol and its end-products. gradient (Smith et al., I958). This process is Reduction of the serum-cholesterol level by facilitated by bile salts, partly at least due to their certain dietary unsaturated fats is unlikely to be emulsifying property. Although pancreatic juice due to diminished synthesis of this sterol: cotton- contains an enzyme which promotes esterification seed oil (Whitney and Roberts, I955), linoleic acid of cholesterol, the pancreas has little influence on (Merrill, I958), corn oil and oleic acid (Wood and the overall rate of cholesterol absorption. The Migicofsky, 1958) increase hepatic cholesterol copyright. esterifying enzyme appears to exert its action in synthesis in the rat. Nor do such oils decrease the intestinal mucosa (Smith et al., I958). The cholesterol absorption (Karvinen et al., 1954). ingestion of unsaturated oils does not suppress Hellman et al. (1957) have invoked an increase in cholesterol absorption (Karvinen et al., 1954) intestinal excretion of cholesterol during corn-oil corn-oil fatty acids, in fact, increase it (Kim and feeding as the mechanism. The importance of Ivy, I952). cholesterol catabolism has been suggested by recent observations on bile acid excretion: in Factors Affecting the Serum-cholesterol short-term, transient-state experiments Level (Gordon http://pmj.bmj.com/ The concentration of cholesterol in the blood et al., I957a; Gordon et al., i957b), the faecal bile shows wide physiological variations, both from acid excretion was found to increase when sun- subject to subject and from time to time in any flowerseed oil was fed, to an extent 1 5 per cent. of one individual. Single determinations in a given that necessary to account for the cholesterol leaving subject are likely to be misleading. Differences in the circulation. In subjects with bile fistulae, analytical technique may also contribute to similarly, cholic acid secretion was markedly in- difficulties in'interpretation. Standard textbooks creased by sunflowerseed-oil feeding before the describe the influence of age, sex, pregnancy, serum cholesterol commenced to fall (Lewis, on October 1, 2021 by guest. Protected climate, time of day and emotional changes on I958b). Cholic acid secretion, which is an index serum-cholesterol levels, though Lindholm (I956) of the rate of catabolism of cholesterol, was also has recently critically assessed some of these increased by intravenous infusion of an emulsion variables. Keys et al. (I950) has analysed a large of cottonseed oil. These findings suggest that number of samples and reported prevailing values certain dietary unsaturated fats reduce the serum in various age-groups. As depicted in Fig. 2, the cholesterol by increasing the rate of catabolism concentration of cholesterol in plasma is the re- of this sterol, at least over short periods of time. sultant of several processes. Of the numerous Byers and Friedman (1958) have provided striking variables influencing these, only diet and the confirmation of this view by means of animal endocrine system will be reviewed, for these are experiments; they administered walnut oil (which the of most intensive research. is highly unsaturated) to normal rats, then can- currently subject nulated the bile ducts and showed increased cholic Diet acid secretion. Evidence was obtained for in- Ahrens (I957) has recently provided a valuable creased cholesterol turnover on feeding this oil. review of the effect of diet on serum lipids. In In our studies, administration of a saturated fat rats, fasting decreases cholesterol synthesis (van did not affect bile acid output. Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from

212 POSTGRADUATE MEDICAL JOURNAL April I959 Relationship of Highly-unsaturated Fatty Acidsto rapidly increases the iodine value to a figure far Cholesterol Metabolism higher than that of the oil itself; dietary sun- While oleic and saturated fatty acids are readily flower-seed oil appears to increase the degree of formed in the body it is thought that'acids with unsaturation of plasma cholesterol ester before two or more double bonds (e.g. linoleic acid) the plasma cholesterol falls (Lewis, I958a). This cannot be synthesized to an important extent by may mean that some cholesterol esters are more mammalian tissues (Lipsky et al., 1957; Reid, readily catabolized than others. Esters obtained I955; Reiser, 1950); certain polyunsaturated from rabbits fed an unsaturated fat are more readily acids can, however, be interconverted (Rieckenhoff hydrolysed than those from animals receiving a et al., I949). Though it has recently been demon- saturated fat (Curran, 1956). Essential fatty acid strated that human erythrocytes can synthesize deficiency in the rat leads to deposition of choles- linoleic and arachidonic acids from acetate (James terol and fat in the liver (Alfin-Slater et al., I954). et al., I957) it has yet to be shown (in the intact Under these conditions, furthermore, much of the animal) that requirements can be met by endo- liver cholesterol becomes esterified with saturated genous synthesis. Linoleic and arachidonic acids fatty acids in place ofoleiciacid (Achaya et al., 1955). behave as vitamins (' essential fatty acids ') in the The proportion of saturated to unsaturated fat nutrition of several animal species (Burr and Burr, in the diet has been invoked as an important aetio- 1929; Deuel, 1955); there is little cogent evidence logical factor in coronary atherosclerosis (Bronte- that this applies to man, but skin lesions have been Stewart et al., I956). While it is well established reported in infants on diets grossly deficient in that the' nature of the dietary fat influences the these acids (Hansen et al., I958). Unsaturated level of cholesterol in the blood, current studies on acids are prominent in all oils which have the plasma cholesterol esters suggest that qualitative property of reducing serum-cholesterol levels. changes may also be important. In a relatively When the intake of essential fatty acids by small survey, plasma cholesterol ester composition certain animals is restricted, the deficiency syn- was compared in patients with coronary heart drome may be precipitated by feeding a saturated disease, normal White and normal Bantu subjectscopyright. fat (Melnick and Deuel, 1954) or cholesterol (Lewis, I958a). The lowest proportion of un- (Peifer and Holman, I955), or by producing hyper- saturated acids was found in the former group, cholesterolaemia by inducing hypothyroidism or while the Bantu (who possess a strikingly im- alloxan diabetes. munity to the disease), had significantly higher At the cellular level, the interplay of fatty acids percentages of linoleic and arachidonic acids. with cholesterol metabolism was shown in a The formation of cholesterol deposits in the fascinating study by Rutstein et al. (1958). These aortae of animals fed this sterol is retarded by workers employed cultures of cells grown from simultaneous administration of unsaturated fats human intima obtained during operations for re- (Kritchevsky, I954; Peiffer and Lundberg, 1957). http://pmj.bmj.com/ section of coarctation of the aorta. When choles- Another important experiment by Kritchevsky terol was present in the medium, intracellular (1956) was to feed rabbits a diet containing choles- lipid deposition occurred; this was accentuated by terol and a fatty acid with either two, one or no the addition of stearic acid (saturated) but was double bonds. The degree of cholesterol deposi- diminished by linolenic acid (three double bonds), tion in the aorta was least when the acid with two an effect being observed with as little as 5 ,tg. per double bonds was fed. This acid was not linoleic cent. of the latter acid. acid but an isomer possessing no essential fatty on October 1, 2021 by guest. Protected Highly unsaturated fatty acids are present in a acid activity. If this observation is confirmed and remarkable concentration in intracellular organelles extended, it would seem that the action of un- (Kretchmer and Barnum, I95i) and as part of the saturated fatty acids on cholesterol metabolism is 'structural lipid' are likely to be of functional not related to their behaviour as essential fatty importance. Availability of such acids may be a acids in animal nutrition. limiting factor in some of the metabolic processes occurring in these structures, conceivably includ- The Unsaponifiable Fraction of Fats ing the conversion of cholesterol to bile acids. Natural fats contain not only triglycerides but The cholesterol esters of plasma contain a pre- also a variable, small proportion of unsaponifiable ponderance of unsaturated fatty acids (Bloor et al., material. This includes the tocopherols, potent 1938; Kelsey and Longenecker, 1941; Lewis, anti-oxidants which protect highly unsaturated I958a). Their fatty acid composition is influenced fatty acids from atmospheric oxidation. Of con- by diet: the iodine value, a measure of unsatura- siderable interest are the sterols, cholesterol in tion, decreases when a fat-free diet or one rich in animal fat and phytosterols such as 3-sitosterol in saturated fat is administered (Kinsell et al., 1958; the seed fats. Following the observation that Lewis, I958a). Feeding certain unsaturated oils P-sitosterol diminishes the hypercholesterolaemia Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from Aprl' I959 LEWIS: The Metabolism of Cholesterol 213 and hepatic cholesterol deposition in chicks fed dition, particularly in the insulin-deficient type, cholesterol (Rosenman et al., 1952), numerous there is an accumulation of acetyl-coenzyme A, experiments have been carried out on human sub- the parent substance inter alia of the ketone bodies jects. Some studies have shown significant reduc- and cholesterol. Increased cholesterol synthesis tion in serum cholesterol (especially if initially occurs in the diabetic rat, and is reduced by high) when large doses of 3-sitosterol are fed fructose administration (Hotta et al., 1954). (Pollak, I952; Beveridge et al., 1957; Barber and Glucagon diminishes the incorporation of acetate Grant, 1955); other workers have found only into cholesterol by liver slices (Hangaard and minor changes (Steiner and Riley, 1955). It Stadie, 1953), though it elevates the serum choles- would appear from fractionation of certain vege- terol slightly (Oliver and Boyd, 1956). Alloxan table oils that part of their effect in reducing the diabetes, like hypothyroidism, accelerates the ap- serum cholesterol is due to the unsaponifiable pearance of the essential fatty acid deficiency fraction (Beveridge et al., I957; Wilkens, I958), syndrome in the rat (Peifer and Holman, 1955); but there is no doubt that potent activity is shown this would appear to be due to the hypercholes- by pure preparations of esters of unsaturated fatty terolaemia increasing the demand for unsaturated acids (Kinsell et al., 1958; Kinsell et al., 1956). fatty acids with which the plasma cholesterol is It is thought that 3-sitosterol, and the similarly esterified. acting dehydrocholesterol interfere with intestinal Adrenal Cortex: Hypofunction leads to a reduc- absorption of cholesterol (Hernandez et al., I953; tion in serum-cholesterol and serum-phosphatide Nichols et al., I953). These sterols are only levels (Di Luzio et al., I954; Selye, I949') Cor- slightly absorbed (Gould, I954), hence they may tisone, prednisone and ACTH conversely, elevate compete with cholesterol for the absorbing cholesterol levels, chiefly affecting the unesterified mechanism. fraction (Wang et al., I955). In atherosclerotic, hypercholesterolaemic men, however, cortisone Endocrine Factors in Cholesterol Metabolism reduces the serum cholesterol (Oliver and Boyd, Thyroid: Hypercholesterolaemia is usual in 1956). In large doses this hormone accelerates the primary myxoedema and coronary heart disease is clearance of postprandial lipaemia (Constantinides copyright. common. Yet cholesterol synthesis is subnormal et al., 1957). In cholesterol-fed rabbits, cortisone in hypothyroidism, both in man (Kurland and further elevates the serum cholesterol but does not Lucas, 1955) and in the rat (Rosenman et al., increase arterial lipid deposition; possible ex- 1952); it is excessive in hyperthyroidism. Choles- planations include diminution of endothelial per- terol turnover is low in myxoedema, as it is in meability (Wang et al., I954). ACTH increases xanthomatosis (Gould, 1958). In mice, thyroxine hepatic cholesterol synthesis (Rosenman et al., increases the rate of catabolism of cholesterol to 1952) but ACTH and cortisone do not affect acidic products (Weiss and Marx, 1955). It is cholic acid secretion, i.e. cholesterol catabolism conceivable that the hypercholesterolaemia in (Rosenman et al., 1952). http://pmj.bmj.com/ myxoedema is due to impaired catabolism of this Pituitary: Hypophysectomy diminishes choles- sterol. terol synthesis in the rat (Tomkins et al., 1952). Recently, the synthetic thyroid hormone ana- Growth hormone (prepared from non-human logue triiodothyroacetic acid (' Triac') has been sources presumably) did not affect the serum investigated in relation to lipid metabolism. In lipids of two normal subjects (Oliver and Boyd, certain tissues oxidative deamination of triiodo- i956). Triac et Sex Hormones: thyronine 'occurs, yielding (Roche al., Coronary heart disease is infre- on October 1, 2021 by guest. Protected 1955). Triac increases the oxygen consumption quent in premenopausal women, while castration of thyroidectomized rats even more rapidly than hastens the development of atheroma in women its parent substance (Trotter, 1956). It remains but retards it in men. The serum-cholesterol to be established, however, that Triac is of physio- and phosphatide levels rise during pregnancy and logical importance. In men with atherosclerosis vary during the menstrual cycle. Women have and hypercholesterolaemia, it has the partly dis- higher a-lipoprotein and lower P-lipoprotein levels sociated effects of reducing the serum cholesterol than age-matched men (Barr et al., 1952). It is without obvious rise in B.M.R. (Oliver and Boyd, thus clear that cholesterol metabolism is pro- 1956), but with an increased incidence of effort foundly influenced by the sex hormones. Species angina (Oliver and Boyd, I957). differences and variations in dosage have ob- Pancreas: Hypercholesterolaemia and hyper- scured the interpretation of much experimental lipaemia are common in diabetes mellitus, often work. Thus oestrogens reduce aortic cholestrol out of proportion to the disturbance in carbo- deposition in rabbits fed this sterol (Ludden hydrate tolerance. The predisposition to athers- et al., 1942), but in large doses produce lipaemia sclerosis is well known. In the uncontrolled con- in rats (Loeb, I942) and lipid deposits in the Postgrad Med J: first published as 10.1136/pgmj.35.402.208 on 1 April 1959. Downloaded from 214 POSTGRADUATE MEDICAL JOURNAL April 959 BLOCH, K., BERG, B. N., and RITTENBERG, D. (1943),, chick aorta (Horlick and Katz, 1948). In men with J. biol. Chem., 149, 51I. hypercholesterolaemia and coronary heart disease, BLOOR, W. R. (1940), Ibid., I32, 77. small doses of oestradiol reduce the serum- BUCHER, N. L. R., and McCARRAHAN, K. (I955), Fed. Proc., 14, 187. cholesterol level and the 3-lipoprotein cholesterol BURR, G. 0., and BURR, M. M. (1929), J. biol. Chem., 82, 345. (OliverandBoyd, 1956). In a recent study on normal BRONTE-STEWART, B., ANTONIS, A., EALES, L., and Furman et al. sex BROCK, J. F. (1956), Lancet, i, 521. and hypogonadsubjectsby (I958), BYERS, S. 0., and FRIEDMAN, M. (1958), Proc. Soc. exp. Biol. hormones had little effect on total cholesterol and (N.Y.), 98, 523. reduced BYERS, S. O., FRIEDMAN, M., and GUNNING, B. (I953), phosphatide levels; but oestrogen p-lipo- Amer. J. Physiol., 175, 375. protein and increased a-lipoprotein concentrations CONSTANTINIDES, P., CAIRNS, A., and SO, Y. (1957), while had the converse effects. Oestro- Canad. J. Biochem. Biophys., 35, 503. androgens COOK. R. P., EDWARDS, 0. C., RIDDELL, C., and gens have been reported to decrease (Tomkins et THOMSON, R. O. (I955), Biochem. J., 6i, 676. al., and to increase (Fillios et al., 1958) COON, M. J. (i955), Fed. Proc., 14, 762. I952) CORNFORTH, J. W., CORNFORTH, R. M., POPJAK, G., and hepatic cholesterol synthesis. They reduce the GORE, I. Y. (1958), Biochem. J., 69, 146. rate of clearance of postprandial lipaemia (Con- CORNFORTH, J. W., and POPJAK, G. (1958), Brit. med. Bull., stantinides et Addition of or I4, 221. al., I957). androgen CURRAN, G. L. (1956), Amer. Pract., 7, 1412. oestrogen to serum in vitro does not alter its lipid DEUEL, H. J., Jnr. (I955), Fed. Proc., 14, 639. or concentrations et al., DI LUZIO, N. R., SHARE, M. L., and ZILVERSMIT, D. B. lipoprotein (Furman 1958). (1954), Metabolism, 3, 424. ECKLES, N. E., TAYLOR, C. B.. CAMPBELL, D. T., and Conclusion GOULD, R. G. (i955), J. Lab. clin. Med., 46, 359. FEIGENBAUM, L.. BYERS. S. O., and FRIEDMAN, M. (I954), Biochemists and clinicians have much cause for Proc. Soc. exp. Biol. (N.Y.), 85, 530. satisfaction in having accumulated so great a body FREDRICKSON, D. S. (1956), J. biol. Chem., 222, o09. FILLIOS, L. C., KAPLAN, R., MARTIN, R. S., and STARE, of information on cholesterol metabolism, largely F. J. (1958), Amer. J. Physiol., 193, 47. in the past decade. It is hoped that the near FRIEDMAN, M., and BYERS, S. 0. (I955), J. clin. Invest., 34, future will a trend towards of 1369. bring integration FRIEDMAN, M., BYERS, S. 0., and MICHAELS, F. (i95i), this mass of data, in the form of unifying concepts Amer. J. 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(i95I), Proc. Soc. exp. Biol. (N.Y.), 78, I43. .Riochem. Biophys., 36, 433. on October 1, 2021 by guest. Protected RUTHIN CASTLE, NORTH WALES A Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The Clinic is provided with a staff of doctors, nurses, technicians, modern Radiological and departments. Physiotherapy The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual rainfall is 30.5 inches, that is less than the average for England. The Fees are inclusive and vary according to the room occupied. For particulars apply to THE SECRETARY, Ruthin Castle, North Wales. Telegrams: Castle, Ruthin Telephone: Ruthin 66