Biblthca Nutr. Dieta, vol. 25, pp. 53-63 (Karger, Basel 1977)
Dietary Fat and Cholesterol Metabolism Α.S. Trustyell Department of Nutrition (Head: Prof. Dr. A.S. Trustyell) , Queen Elizabeth College, London University, London
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We have, in practice, to take the concentration of total cholesterol in plasma as the index of the amount of metabolically important cholesterol in the body. Plasma cholesterol is in equilibrium with other tissue pools — a rapidly turning over pool (liver, red cell, intestine) and a larger, slowly turning over tissue pool. Plasma cholesterol (3.0 1 X 2,300 mg/1) totals some 7 g, while the total amount in the body, excluding the brain, has been estimated at 108 g (for a 70-kg man) (1). Plasma cholesterol concentration correlates poorly, if at all, with the slowly turning over tissue pools, but it is related to the turnover rate of cholesterol in the rapidly turning over tissue pool (2). Plasma cholesterol concentration is the only index about which there are extensive data because it is by far the easiest and the traditional way to measure cholesterol in the body. It is also the only one which is firmly extablished to correlate strongly with the lipid in arterial intima (3) and with the risk of pathological atherosclerosis (4, 5) and clinical atherosclerotic disease, CHD (6), intermittent claudication (7) and to a smaller degree cerebral vascular disease (8). In monkeys with dietary hypercholesterolaemia Armstrong et al. (9) found the concentration of cholesterol compared with controls, 5 X in plasma, 7 X in aorta, 5 X in tendon, 4.5 X in liver, but in other organs the concentrations ranged from 2 X to 1 X (in brain). When deciding whether plasma cholesterol is high enough to be treated, e.g. by diet, and in assessing the effect of such treatment, difficulties can arise from two types of variation, biological and technical. Biological causes of low cholesterol include severe illness, including myocardial infarction, anaemia and some drugs (10) while pregnancy, some oral contraceptives, certain other drugs (10) and sometimes mental tension can increase plasma cholesterol. Venostasis and standing also produce a modest increase. Seasonal variations appear to occur, with lower concentrations in summer. In the routine chemical pathology laboratory technical variation is considerable (11, 12), but some methods are more reliable, especially the manual Abell method and the Technicon 124Α auto-
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mated method. Because of the intra-individual variations (13), it is now standard practice in hyperlipidaemia clinics that no patient should be started on a cholesterol-lowering regime until his plasma cholesterol has been measured three times by a good laboratory method, with the patient in a steady state. Cholesterol in plasma is about 70% esterified. The pattern of fatty acids in cholesterol esters is around 45-50% linoleate and 25% oleate, but this can be modified by diet. On a high polyunsaturated fat diet, the linoleate is increased (14) and in EFA deficiency it falls to 10%ο or less (15). Cholesterol in plasma is carried chiefly on low-density lipoprotein (LDL) or ß-lípoprotein (Sf 0-12) which contains 45% cholesterol. Some 1.3 mmol/l (50 mg/100 ml) is contributed by high-density lipoprotein (HDL) or α-liρoprotein (which contains 20% of cholesterol). Most conditions which affect the plasma (total) cholesterol, including diet, do so by affecting the concentration of ß (LDL + VLDL) cholesterol, not the HDL or οι-lípoprotein (16, 17). The few conditions that influence HDL cholesterol are sex hormones, severe kwashiorkor (18), severe renal failure (19), exposure to organochlorine insecticides (20) and the inborn error, Tangier disease. HDL differs in another important way from LDL: it may be protective against atherosclerosis (21). The amount of cholesterol in chylomicrons is so small (5%) that blood may be used for cholesterol measurement after a meal containing fat (20) with very little error. There is about 10% of cholesterol in very low density lipoprotein (VLDL) (pτe-ß-lipoprotein) as against 60-80 of triglycerides (for comparison, LDL contain 10% of triglycerides). Consequently, it is possible to estimate the amount of VLDL cholesterol when plasma triglycerides are increased (23). LDL cholesterol = plasma cholesterol —triglyceride/5 —HDL cholesterol. The picture is becoming clearer of the inter-relationships between the 4 main groups of plasma lipoproteins. There are transfers both of lipids and of apolipoproteins (24). VLDL is secreted by the liver containing mostly apolipoprotein (apo)B. The nascent VLDL picks up apo C in the plasma. VLDL then contains about equal amounts of αρο B and αρο C. In plasma, its cholesterol is esterified by LCAT, which needs the αρο A of HDL as co-factor. VLDL loses most of its triglycerides by the action of lipoprotein lipase (which needs αρο C11 as co-factor) and becomes, first, `intermediate lipoprotein' (Sf 12-20). It loses its αρο C as it loses more TG and ends up as LDL (Sf0-12) with predominantly αρο B. Chylomicrons also contain αρο B and αρο C and appear to undergo similar transformation to VLDL. Dietary Glycerides and Plasma Cholesterol
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As early as 1916, De Langen (25) reported that plasma cholesterols in healthy Javanese men were much lower than in Netherlands, France or Germany and suggested that this was because their diet was low in cholesterol and other
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Dietary Fat and Cholesterol Metabolism
Table L. Effects of different dietary fatty acids on plasma cholesterol and triglycerides, as demonstrated in acute experiments in man Dietary fatty acid
MCT, Cg .η to C,η ,η
Lauric, C, Z ,o Myristic, C,,,o Palmitic, C, b , o Stearic, C13, 0 Oleic, C, R; ι Linoleic, C,„,Ζ Other polyunsaturated
Plasma cholesterol
triglycerides
0
t 0 0 0 1 0 1 ?
Γ
11 1t ?1 0 1 1 (? )
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lipids. Little progess was made between then and the early 1950s. This was partly because exogenous cholesterol has only a small and variable effect on plasma cholesterol in man. Then in quick succession it was shown that human plasma cholesterol is increased by total dietary fat (1952) (26), by animal fat (1952) (27), and saturated fat (1956) (17). Work done since then makes it possible to go further and describe the contribution of individual fatty acids in dietary triglycerides. Our present knowledge is summarised in table I. This information has been provided by three laboratories, Keys and Grande's group in Minnesota (28a, b), the Nutrition Deparment at the Harvard School of Public Health (29, 30) and by workers at Unilever Research in Holland (31). In general, saturated fats have a stronger elevating effect than the cholesterollowering effect of linoleic acid, but the effect of saturated fats is mainly due to palmitic acid which is more abundant in dietary fats than is myristic acid. Chain length thus partly determines the activity. Medium chain triglycerides, though saturated, do not increase plasma cholesterol and, surprisingly, all three research groups find that stearic acid has far less elevating effect than palmitic. (For comparison, the effect of these fatty acids on plasma endogenous triglycerides are included in table I.) There have been some inconsistencies; distribution of fatty acids between the triglycerides may have some influence, as may the total fat intake, but the picture from the three laboratories is really quite consistent. It has been suggested that cis-trans isomerism has an effect, which would be important in hydrogenated fats, such as margarine (32). Put briefly, the workers at Unilever Research (33) report that trans 18:1 (elaidic) acid increases plasma cholesterol. But the group at Proctor and Gamble disagree (34). The explanation appears to lie in the amounts fed. Amounts which might be eaten in margarine in ordinary life do not affect plasma cholesterol, but very large intakes do.
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How do polyunsaturated fats lower plasma cholesterol, or perhaps the better question, how does palmitic acid raise it? The more one goes into the experimental technology required, the more complicated and difficult it becomes. Specialists in the field have been divided into two camps, those like Grundy and Ahrens (35), who found the increase of faecal bile acids (or neutral steroids) when saturated fats were replaced by polyunsaturated insufficient to account for the reduction in plasma cholesterol, and the others who find increased excretion themselves and argue that negative results have occurred mostly in patients with type II hyperlipidaemia, who have a special abnormality in cholesterol catabolism (36). Reduction of plasma triglycerides also occurs on polyunsaturated fat diets, and Lewis and Chait (37) have evidence that this may be due to decreased VLDL synthesis. Since VLDL is eventually converted into LDL, decreased synthesis may be an additional mechanism for the effect of polyunsaturated fats. This has been reported in the livers or experimental animals (38). A recent British report on priorities in nutrition research (39) includes among its recommendations: `It is important that the mechanism of action of the polyunsaturated acids should be elucidated ...' Recently, Grundy (40) reports clearly increased faecal bile acids and endogenous neutral steroids on polyunsaturated fat diets in patients with hypertriglyceridaemia. The foregoing is what happens in a metabolic unit, often with liquid formula diets and sometimes semi-synthetic fats. With natural foods and freeliving people, many other variables come into play. Correlations between dietary fatty acid pattern and plasma cholesterol can be considered at two levels correlation between groups of people of different cultures and correlations within a group of people having the same culture. Most of the differences between the mean plasma cholesterol of the different nations and ethnic groups in the world can be explained by differences in their consumption of dietary fats (41, 42). In a study of 9 different groups in southern Africa, we found the correlation between serum TG linoleic acid and plasma cholesterol was —0.34 (43). There are a small number of apparent exceptions. The best known are the Masai in East Africa. The young men of this tribe eat large amounts of milk and blood, but have plasma cholesterols averaging only 3.1 mmol/1 (120 mg/100 ml). Several observations have been put forward to explain this paradox. The Masai take a lot of exercise (44), they are lean and do not necessarily eat a high fat diet all the year round (45), they appear to have an efficient feedback mechanism for suppressing endogenous cholesterol synthesis on a high cholesterol intake (46) and the fat in fermented milk may have a different metabolic effect from butter fat as eaten, for example, in Europe (47). But when plasma cholesterols and dietary fat have been compared within a group of people who all have a similar way of life, significant correlations were not found (48, 49). To put these findings in perspective, there was no correlation either between the estimate of dietary iron and the haemoglobin levels in
Dietary Fat and Cholesterol Metabolism
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the Framingham study (49). There are methodological weaknesses in the reported studies. For example, in Morris et al.'s (48) study of London bank men, there were varying intervals between the diet survey and taking blood, and 2 different cholesterol methods were used. In Framingham, the diet was estimated only from an interview intended to elicit usual intake (49) and then calculated from food tables. But even with better dietary measurements, weighing actual food consumed and analysing the foods for fatty acids, plasma cholesterol has not correlated with dietary fat (42). Repeat dietary measurements show that the variation of intake in the same individual is of the same magnitude as that between individuals (42). These dietary variations are too great for the small mean differences between individuals to show and it is known that on the same diet there are differences in plasma cholesterol between individuals, which must be constitutional. The only clear demonstration of correlation between dietary fat and plasma cholesterol was made in the members of an Antartic expedition; diet was measured 8 times and plasma cholesterol 12 times. The fat was mainly saturated and the correlation between fat calories and serum cholesterol was + 0.53 (50). Nevertheless, within a couple of weeks after starting a diet low in saturated fat and with increased polyunsaturated fat, people who have been on a usual European or North American diet will all show a fall of 10% or more in plasma cholesterol, which stays at the new, lower level as long as the therapeutic diet is continued, and for at least 8 years (51, 52). Only some cases of type lIA hyperlipidaemia are resistent. Note that those who start with higher cholesterols in a group stay higher than average in their group although they often show a greater absolute fall in plasma cholesterol (51).
Dietary Sterols and Plasma Cholesterol
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Different species of animals vary greatly in their response to dietary cholesterol. Massive hypercholesterolaemia is produced in rabbits fed cholesterol, while rats show little change unless they are given cholic acid as well, to inhibit the compensatory increase in bile acid production. For a long time, the effect in man was not clear. Keys et al. (53) maintained that dietary cholesterol had no effect and, as recently as 1969, a reputable textbook (54) was stating: `The dietary cholesterol has a negligible effect on plasma levels. Even eating ten eggs a day ... does not usually raise the level of plasma cholesterol.' With the accumulation of more experimental data, it is now accepted that exogenous cholesterol increases the plasma concentration (55). There are, however, three characteristics of the relationship. The effect is smaller than that of saturated fats; the response is non-linear, with the first 200-300 mg having a
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greater effect; thirdly, there is probably more individual variability than with dietary glycerides. Absorption of cholesterol is limited in man, from 50% at very low intakes, down to 10% at high intakes. Inefficiency and variability of absorption is one reason why plasma cholesterol only increases by small amounts; the other is that hepatic cholesterol synthesis is inhibited when plasma cholesterol tends to rise (56). However, the pools can accumulate 20 g of cholesterol in some subjects before the switch-off occurs (57). This feedback varies rather widely between different individuals (58) and possibly between different populations (46). In normal diets, there are sterols other than cholesterol. Sea foods usually contain 24-methylene-cholesterol as well. Plant lipids contain no cholesterol but a variety of phytosterols, such as ß-sitosterol (24-ethyl-cholesterol). We know most about the biological effects of this one. It lowers plasma cholesterol in man, mainly by competitive inhibition of absorption and reabsorption (57), but a small amount of phytosterols is absorbed (59) and may have systemic actions. Two rare cases have even been reported in which ß-sitοsterol accumulated in tendon xanthomas (60). ß-Sitosterol was marketed by Eli Lilly some years ago as a cholesterollowering agent under the trade name `Cytellín'. The dose is 3-6 g thrice daily (61, 62). The amounts in commercially refined vegetable oils are much smaller than this; the unsaponifiable fraction is usually under 1%. Of course, there are other dietary components that influence plasma cholesterol, particularly the energy (calorie) balance (63) some of the `dietary fibre' (64), possibly some saponíns (65), vitamin D (66), meal frequency (67), etc., but their effects are usually less than that of the dietary glycerides. Some Practical Implications
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(A) In working out a therapeutic diet for patients with hypercholesterolaemia, there are several unanswered questions: How important is dietary cholesterol? For example, liver contains 250300 mg cholesterol/100 g, compared with 500 mg in eggs, 100 mg in beef and 75 mg in chicken. Where should the line be drawn between allowing and forbidding? There is incomplete information about shellfish. Some advise that they should be avoided because of high cholesterol content, but the small amount of modern data show that the cholesterol is about the same as in meat, and in some shellfish an important proportion are other sterols, not well identified (68). Should peanuts and peanut butter be encouraged or discouraged? The arachidic and behenic acids they contain do not particularly raise the plasma cholesterol, but appear to be an atherogenic in animals (69, 70).
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How freely may egg whites be used? Could large amounts cause biotin deficiency? (B) What should be the ideal diet for the general population of Western countries, as one contribution to reducing the very high rates of CHD? In Finland, Norway, Sweden and the Medical Boards (71) recommend reduced fat intake, 25-35%, with an increased proportion of polyunsaturated fats. Also, more fruit and vegetables, etc. and more exercise. The Netherlands Nutrition Board (72) recommend that dietary total fat be reduced to about 33% of calories with linoleic acid increased to about 10-13% of calories. The British Department of Health Committee on Medical Aspects of Food Policy (73) agree that the fat intake of the general population should be reduced from the present 42% of calories, especially saturated fat, but do not recommend increasing polyunsaturated fat from the present 5% of calories. I am sure there is no single ideal diet. There are many good diets, which differ with a group's cultural traditions and the availability of foods. (There are also many bad diets.) There are, I believe rightly, still some reservations about the long-term safety of high intakes of polyunsaturated fats (74), which give more anxiety in some countries than others. These will be answered by more long-term research. All are agreed that saturated fats should be decreased. If people are not to lose weight they will have to replace these with either polyunsaturated oils, or starchy foods or mono-unsaturated fats like olive oil. There is very little CHD in the Southern Mediterranean, e.g. in Crete, where this is the main dietary fat (42, 75). Possibly the best would be a combination of the three. (C) These recommendations that are now being made will not be economically feasible unless they are integrated with agricultural policies and planning. Do we wish to see the egg industry run down and chicken production increased? Do we mean that butter should be replaced by either margarine rich in linoleic acid or made from the milk of cows fed with protected polyunsaturated fat? How can Europe produce enough polyunsaturated fat in its own fields to meet the demands of these recommendations? Should fish farming be encouraged and should this include shellfish? The food industry will be affected, and labelling regulations and people's food habits. It seems to me that we European nutritionists will soon have to consider the many practical implications of these recommendations about the ideal diet, as has been started in the USA (76) and in Australia (77). References
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Cook, R.P. (ed.): Cholesterol, p. 174 (Academic Press, New York 1958). Goodman, D.S.: The measurement of cholesterol pools and turnover in man; in Jones Atherosclerosis. Proc. 2nd Int. Symp., pp. 242-248 (Springer, Berlin 1970). Smith, E.B. and Slater, R.S.: Relationship between plasma lipids and arterial tissue lipids. Nutr. Metabol. 15: 17-26 (1973). Downloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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Truswell Scrimshaw, N.S. and Guzman, M.A.: Diet and atherosclerosis. Lab. Invest. 18: 623-628 (1968). Schwartz, C.J.; Stenhouse, N.S.; Taylor, Α.Ε. , and White, T.A.: Coronary disease severity at necropsy. Br. Heart J. 27: 731-739 (1965). Dayton, S.: Rationale for use of lipid-lowering drugs. Fed. Proc. Fed. Am. Socs exp. Biol. 30: 849-856 (1971). Gordon, T. and Kanne!, W.B.: Predisposition to atherosclerosis in the head, heart, and legs. J. Am. med. Ass. 221: 661--666 (1972). Greenhouse, A.H.: Blood lipids and strokes — are they related? J. chron. Dis. 23. 823-828 (1971). Armstrong, M.L.; Connor, W.E., and Warner, E.D.. Tissue cholesterol concentration in the hypercholesterolemic Rhesus monkey. Archs Path. 87: 87-92 (1969). Truswell, A.S.: Drugs and lipid metabolism. Proc. Nutr. Soc. 33: 215--224 (1974). Whitehead, T.P.; Browning, D.M., and Gregory, A.: A comparative survey of the results of analyses of blood serum in clinical chemistry laboratories in the United Kingdom. J. clin. Path. 26: 435-445 (1973). Schwartz, M.K. and Hill, P.: Problems in the interpretation of serum cholesterol values. Prey. Med. 1: 167--177 (1972). Keys, A. and Fidanza, F.: Serum cholesterol and relative body weight of coronary patients in different populations. Circulation 22: 1091-1106 (1960). Arvidson, G. and Malmros, H.: Studies on the influence of dietary fat on the fatty acid composition of serum lipids on humans. Z. ErnahrWiss. 11: 105-119 (1972). Paulsrud, J.R.; Pensler, L.; Whitten, CF; Stewart, S., and Holman, R.T.: Essential fatty acid deficiency in infants induced by fat-free intravenous feeding. Am. J. clin. Nutr. 25: 897-904 (1972). Franzini, C. and Schivi, T.: On the distribution of serum cholesterol between o- and ß-lipoproteins. Clin. chim. Acta 9: 87-89 (1964). Brunte-Stewart, B.; Antonis, A.; Eales, L., and Brock, J.F.: Effects of feeding different fats on serum cholesterol level. Lancet i: 521-526 (1956). Truswell, A.S., Hansen, J.D.L.; Watson, CE., and Wannenburg, P.: Relation of serum lipids and lipoproteins to fatty liver in kwashiorkor. Am. J. clin. Nutr. 22: 568 -576 (1969). Lewis, L.A.; Zuehlke, V.; Nakamoto, S.; Kolff, W.J., and Page, I.H.: Renal regulation of serum ‚s-lipoproteins. Decrease of α-lipoproteins in the absence of renal function. New Engl. J. Med. 275: 1097-1100 (1966). Carlson, L.A. and Kolmodin-Hedman, B.: Hyper-o-lipoproteinemia in men exposed to chlorinated hydrocarbon pesticides. Acta med. scand. 192: 29-32 (1972). Miller, G.J. and Miller, Ν.Ε. : Plasma-high-density lipoprotein concentration and development in ischaemic heart disease. Lancet i: 16-19 (1975). Hollister, L.Ε. and Wright, A.: Diurnal variation of serum lipids. J. Atheroscler. Res. 5. 445-450 (1956). Friedewald, W.T.; Levy, R.I., and Fredrickson, D.S.: Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin. Chem. 18: 499-502 (1972). Fredrickson, D.S.: Plasma lipoproteins and apolipoproteins. Harvey Lect. 68: 185-237 (1974). De Langen, C.D.: Cholesterike-stoffwisselrng en rassenpathologie. Geneesk Tijdschrift Nederl-Indie 26: 1-34 (1916). Keys, A.: Human atherosclerosis and the diet. Circulation 5: 115-118 (1952). Kinsell, L. W.; Partridge, J.; Boling, L.; Margen, S., and Michaels, G.: Dietary modificaDownloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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tun of serum cholesterol and phospholipid levels. J. clan. Endocr. 12: 909-913 (1952). 28a Grande, F.; Anderson, J. T., and Keys, Α.: Comparison of effects of palmitic and stearic acids in the diet on serum cholesterol in man. Am. J. clin. Nutr. 23: 1184-1193 (1970). 28b Grande, F.; Anderson, J.T., and Keys, Α.: Diets of different fatty acid composition producing identical serum cholesterol levels in man. Am. J. clin. Nutr. 25: 53-60 (1972). 29 Hegsted, D.M.; McGandy, R.B.; Myers, M.L., and Stare, F.J.: Quantitative effects of dietary fat on serum cholesterol in man. Am. J. clin. Nutr. 17: 281-295 (1965). 30 McGandy, R.B.; Hegsted, D.M., and Myers, M.L.: Use of semisynthetic fats in determining effects of specific dietary fatty acids on serum lipids in man. Am. J. clin. Nutr. 23: 1288-1298 (1970). 31 Vergroesen, A.J. and De Boer, J.: Effecten van meervoudig onverzadigde en andere vetzuren in de voeding. Voeding 32: 278-290 (1971). 32 Anderson, J.T.; Grande, F., and Keys, Α.: Hydrogenated fats in the diet and lipids in the serum of man. J. Nutr. 75: 388-394 (1961). 33 Vergroesen, A.J.: Dietary fat and cardiovascular disease: possible modes of action of linoleic acid. Proc. Nutr. Soc. 31: 323-329 (1972). 34 Mattson, F.H.; Hollenbach, E.J., and Kligman, Α.M.: Effect of hydrogenated fat on the plasma cholesterol and triglyceride levels of man. Am. J. clin. Nutr. 28: 726-731 (1975). 35 Grundy, S.M. and Ahrens, E.H., jr.: The effects of unsaturated dietary fats on absorption, excretion, synthesis and distribution of cholesterol in man. J. clin. Invest. 49: 1135-1152 (1970). 36 Connor, W.E.: The effects of dietary lipid and sterols on the sterol balance; in Jones Atherosclerosis, Proc. 2nd Int. Symp., pp. 253-261 (Springer, Berlin 1970). 37 Lewis, B.: Personal commun. (1975). 38 Bartley, J. and Abraham, S.: Effect of dietary fats of different fatty acid composition on hepatic lipogenesis in rats and mice. 9th Int. Congr. Nutrition, Mexico 1972, abstr., p. 67. 39 Agricultural Research Council/Medical Research Council: Food and Nutrition Research. Report of the ARC/MRC Committee, p. 130 (HMSO, London 1974). 40 Grundy, S.M.: Effects of polyunsaturated fats on lipid metabolism in patients with hyperlipidemia. J. clin. Invest. 55: 269-282 (1975). 41 Gordon, H.: The regulation of the human serum cholesterol. Postgrad. med. J. 35: 186-196 (1959). 42 Keys, A. (ed.): Coronary heart disease in seven countries. Circulation 41: suppl. 1, pp. 1-211 (1970). 43 Truswell, A.S. and Mann, J.1.: Epidemiology of serum lipids in southern Africa. Atherosclerosis 16: 15-29 (1972). 44 Mann, C. V.; Shaffer, R.D., and Rich, A.: Physical fitness and immunity to heartdisease in Masai. Lancet íi: 1308-1310 (1965). 45 Shaper, A.G.: Cardiovascular disease in the tropics. IV. Coronary Heart Disease. Br. med. J. iv: 32-35 (1972). 46 Ho, K.J.; Biss, K.; Mikkelson, B.; Lewis, L.A., and Taylor, CB.: The Masai of East Africa: some unique biological characteristics. Archs Path. 91: 387-410 (1971). 47 Mann, G. V. and Spoerry, A.: Studies of a surfactant and cholesteremia in the Masai. Am. J. clin. Nutr. 27: 464-469 (1974). 48 Morris, J.N.; Marr, J.W.; Heady, J.A.; Mills, G.L., and Pilkington, T.R.E.: Diet and plasma cholesterol in 99 bank men. Br. med. J. i: 571-576 (1963).
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Kannel, W.B. and Gordon, T.: The Framingham Study. An epidemiological investigatun of cardiovascular disease; sect. 24. The Framingham diet study: diet and the regulation of serum cholesterol (US Government Printing Office, Washington 1970). 50 Easty, D.L.: The relationship of diet to serum cholesterol levels in young men in Antartica. Br. J. Nutr. 24: 307-312 (1970). 51 Leren, P.: The effect of plasma cholesterol-lowering diet in male survivors of myocardial infarction. Acta med. scand. Suppl. 466: 1-92 (1966). 52 Dayton, S.; Pearce, M.L.; Hashimoto, S.; Dixon, W.J., and Tomiyasu, U.: A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 39/40: suppl. II, pp. 1-62 (1969). 53 Keys, Α.; Anderson, J.T.; Mickelson, O.; Adelson, S.F., and Fidanza, F.: Diet and serum cholesterol in man: lack of effect of dietary cholesterol. J. Nutr. 59: 39-56 (1956). 54 Davidson, S. and Passmore, R.: Human nutrition and dietetics; 4th ed., p. 102 (Livingstone, Edinburgh 1969). 55 Keys, A.; Grande, F., and Anderson, J.T.: Bias and misrepresentation revisited: perspective on saturated fat. Am. J. clin. Nutr. 27: 188-212 (1974). 56 Dietschy, J.M. and Wilson, J.D.: Regulation of cholesterol metabolism. New Engl. J. Med. 282: 1128-1138, 1179-1185, 1241-1249 (1970). 57 Grundy, S.M.; Ahrens, E.H., jr., and Davignon, J.: The interaction of cholesterol absorption and cholesterol synthesis in man. J. Lipid Res. 10: 304-315 (1969). 58 Quintdo, E.; Grundy, S.M., and Ahrens, E.H., jr.: Effects of dietary cholesterol in the regulation of total body cholesterol in man. J. Lipid Res. 12: 233-247 (1971). 59 Ravi Subbiah, M.T.: Dietary plant sterols — current status in human and animal sterol metabolism. Am. J. clin. Nutr. 26: 219-225 (1973). 60 Bhattacharyya, A.K. and Connor, W.E.: β-Sitοsterolemia and xanthomatosis: a newly described lipid storage disease in two sisters. J. clin. Invest. 52: 9A (1973). 61 Best, M.M.; Duncan, C.H.; Loon, E.J. Van, and Wathen, J.D.: The effects of sitosterol on serum lipids. Am. J. Med. 19: 61-70 (1955). 62 Farquhar, J. W. and Sokolow, M.: Response of serum lipids and lipoproteins of man to beta sitosterol and safflower oil. A long-term study. Circulation 17: 890-899 (1958). 63 Pincherle, G.: Factors affecting the mean serum cholesterol. J. chron. Dis. 24: 289297 (1971). 64 Trustyell, A.S. and Kay, R.M.: Absence of effect of bran on blood lipids. Lancet i: 922-923 (1975). 65 Birk, Y.: Saponins; in Liener Toxic constituents of plant foodstuffs, pp. 169-210 (Academic Press, New York 1969). 66 Linden, V.: Vitamin D and myocardial infarction. Br. med. J. iii: 647-650 (1974). 67 Gwinup, G.; Byron, R C.; Roush, W.H.; Kruger, F.A., and Harnwj, G.J.: Effect of nibbling versus gorging on serum lipids in man. Am. J. clin. Nutr. 13: 209-213 (1963). 68 Feeley, R.M.; Criner, P.E., and Watt, B.K.: Cholesterol content of foods. J. Am. diet. Ass. 61: 134-149 (1972). 69 Howard, A.N. and Gresham, G.A.: Dietary aspects of atherosclerosis and thrombosis. Int. Z. VitamForsch. 38: 545-559 (1968). 70 Kritchevsky, D.; Tepper, S.A.; Vesselinovitch, D., and Wissler, R. W.: Cholesterol vehicle in experimental atherosclerosis. 13. Randomized peanut oil. Atherosclerosis 17: 225-243 (1973). 71 Combined Medical Boards of Finland, Norway and Sweden: Medicinsky synpunkter på folkkosten i de nordiska landerna (1969); quoted by Davidson, Passmore, Brock and Downloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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Truswell Human nutrition and dietetics; 6th ed., p. 652 (Churchill/Livingstone, Edinburgh/London 1975). 72 Voedingsraad: Advies over hoeveelheid en/of aard der vetten in de voeding. Volksgesondheid 25, Ministerie van Volksgesondheid en Milieuhygiene (Staatsuitgeverij, 's-Gravenhage 1973). 73 Department of Health and Social Security: Diet and coronary heart disease. Report of the Advisory Panel of the Committee on Medical Aspects of Food Policy (Nutrition). Report on health and social subjects, vol. 7 (HMSO, London 1974). 74 Truswell, A.S.: Fats and fatty oils: nutritional and medical aspects. Reports on the progress of applied chemistry during 1973, vol. 58, pp. 459-470 (Academic Press, New York 1975). 75 Christakis, G.; Severinghaus, E.L.; Maldonado, Z.; Kafatos, F.C., and Hashím, S.A.: Crete: a study in the metabolic epidemiology of coronary heart disease. Am. J. Cardiol. 15: 320-332 (1965). 76 Symposium: Developing foods for the cardiac-concerned. Food Technol. 1974: 16-32. 77 Food, fats and heart disease: Conf. on Changing Food Habits. Food Technol. Aust. 26: Suppl. 9, pp. 385-431 (1974).
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Prof. Dr. A.S. Truswell, Department of Nutrition, Queen Elizabeth College, University of London, Campden Hill, London W8 7ΑΗ (England)
Dietary Fat and Cholesterol Metabolism Α.S. Trustyell Department of Nutrition (Head: Prof. Dr. A.S. Trustyell) , Queen Elizabeth College, London University, London
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We have, in practice, to take the concentration of total cholesterol in plasma as the index of the amount of metabolically important cholesterol in the body. Plasma cholesterol is in equilibrium with other tissue pools — a rapidly turning over pool (liver, red cell, intestine) and a larger, slowly turning over tissue pool. Plasma cholesterol (3.0 1 X 2,300 mg/1) totals some 7 g, while the total amount in the body, excluding the brain, has been estimated at 108 g (for a 70-kg man) (1). Plasma cholesterol concentration correlates poorly, if at all, with the slowly turning over tissue pools, but it is related to the turnover rate of cholesterol in the rapidly turning over tissue pool (2). Plasma cholesterol concentration is the only index about which there are extensive data because it is by far the easiest and the traditional way to measure cholesterol in the body. It is also the only one which is firmly extablished to correlate strongly with the lipid in arterial intima (3) and with the risk of pathological atherosclerosis (4, 5) and clinical atherosclerotic disease, CHD (6), intermittent claudication (7) and to a smaller degree cerebral vascular disease (8). In monkeys with dietary hypercholesterolaemia Armstrong et al. (9) found the concentration of cholesterol compared with controls, 5 X in plasma, 7 X in aorta, 5 X in tendon, 4.5 X in liver, but in other organs the concentrations ranged from 2 X to 1 X (in brain). When deciding whether plasma cholesterol is high enough to be treated, e.g. by diet, and in assessing the effect of such treatment, difficulties can arise from two types of variation, biological and technical. Biological causes of low cholesterol include severe illness, including myocardial infarction, anaemia and some drugs (10) while pregnancy, some oral contraceptives, certain other drugs (10) and sometimes mental tension can increase plasma cholesterol. Venostasis and standing also produce a modest increase. Seasonal variations appear to occur, with lower concentrations in summer. In the routine chemical pathology laboratory technical variation is considerable (11, 12), but some methods are more reliable, especially the manual Abell method and the Technicon 124Α auto-
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mated method. Because of the intra-individual variations (13), it is now standard practice in hyperlipidaemia clinics that no patient should be started on a cholesterol-lowering regime until his plasma cholesterol has been measured three times by a good laboratory method, with the patient in a steady state. Cholesterol in plasma is about 70% esterified. The pattern of fatty acids in cholesterol esters is around 45-50% linoleate and 25% oleate, but this can be modified by diet. On a high polyunsaturated fat diet, the linoleate is increased (14) and in EFA deficiency it falls to 10%ο or less (15). Cholesterol in plasma is carried chiefly on low-density lipoprotein (LDL) or ß-lípoprotein (Sf 0-12) which contains 45% cholesterol. Some 1.3 mmol/l (50 mg/100 ml) is contributed by high-density lipoprotein (HDL) or α-liρoprotein (which contains 20% of cholesterol). Most conditions which affect the plasma (total) cholesterol, including diet, do so by affecting the concentration of ß (LDL + VLDL) cholesterol, not the HDL or οι-lípoprotein (16, 17). The few conditions that influence HDL cholesterol are sex hormones, severe kwashiorkor (18), severe renal failure (19), exposure to organochlorine insecticides (20) and the inborn error, Tangier disease. HDL differs in another important way from LDL: it may be protective against atherosclerosis (21). The amount of cholesterol in chylomicrons is so small (5%) that blood may be used for cholesterol measurement after a meal containing fat (20) with very little error. There is about 10% of cholesterol in very low density lipoprotein (VLDL) (pτe-ß-lipoprotein) as against 60-80 of triglycerides (for comparison, LDL contain 10% of triglycerides). Consequently, it is possible to estimate the amount of VLDL cholesterol when plasma triglycerides are increased (23). LDL cholesterol = plasma cholesterol —triglyceride/5 —HDL cholesterol. The picture is becoming clearer of the inter-relationships between the 4 main groups of plasma lipoproteins. There are transfers both of lipids and of apolipoproteins (24). VLDL is secreted by the liver containing mostly apolipoprotein (apo)B. The nascent VLDL picks up apo C in the plasma. VLDL then contains about equal amounts of αρο B and αρο C. In plasma, its cholesterol is esterified by LCAT, which needs the αρο A of HDL as co-factor. VLDL loses most of its triglycerides by the action of lipoprotein lipase (which needs αρο C11 as co-factor) and becomes, first, `intermediate lipoprotein' (Sf 12-20). It loses its αρο C as it loses more TG and ends up as LDL (Sf0-12) with predominantly αρο B. Chylomicrons also contain αρο B and αρο C and appear to undergo similar transformation to VLDL. Dietary Glycerides and Plasma Cholesterol
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As early as 1916, De Langen (25) reported that plasma cholesterols in healthy Javanese men were much lower than in Netherlands, France or Germany and suggested that this was because their diet was low in cholesterol and other
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Dietary Fat and Cholesterol Metabolism
Table L. Effects of different dietary fatty acids on plasma cholesterol and triglycerides, as demonstrated in acute experiments in man Dietary fatty acid
MCT, Cg .η to C,η ,η
Lauric, C, Z ,o Myristic, C,,,o Palmitic, C, b , o Stearic, C13, 0 Oleic, C, R; ι Linoleic, C,„,Ζ Other polyunsaturated
Plasma cholesterol
triglycerides
0
t 0 0 0 1 0 1 ?
Γ
11 1t ?1 0 1 1 (? )
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lipids. Little progess was made between then and the early 1950s. This was partly because exogenous cholesterol has only a small and variable effect on plasma cholesterol in man. Then in quick succession it was shown that human plasma cholesterol is increased by total dietary fat (1952) (26), by animal fat (1952) (27), and saturated fat (1956) (17). Work done since then makes it possible to go further and describe the contribution of individual fatty acids in dietary triglycerides. Our present knowledge is summarised in table I. This information has been provided by three laboratories, Keys and Grande's group in Minnesota (28a, b), the Nutrition Deparment at the Harvard School of Public Health (29, 30) and by workers at Unilever Research in Holland (31). In general, saturated fats have a stronger elevating effect than the cholesterollowering effect of linoleic acid, but the effect of saturated fats is mainly due to palmitic acid which is more abundant in dietary fats than is myristic acid. Chain length thus partly determines the activity. Medium chain triglycerides, though saturated, do not increase plasma cholesterol and, surprisingly, all three research groups find that stearic acid has far less elevating effect than palmitic. (For comparison, the effect of these fatty acids on plasma endogenous triglycerides are included in table I.) There have been some inconsistencies; distribution of fatty acids between the triglycerides may have some influence, as may the total fat intake, but the picture from the three laboratories is really quite consistent. It has been suggested that cis-trans isomerism has an effect, which would be important in hydrogenated fats, such as margarine (32). Put briefly, the workers at Unilever Research (33) report that trans 18:1 (elaidic) acid increases plasma cholesterol. But the group at Proctor and Gamble disagree (34). The explanation appears to lie in the amounts fed. Amounts which might be eaten in margarine in ordinary life do not affect plasma cholesterol, but very large intakes do.
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How do polyunsaturated fats lower plasma cholesterol, or perhaps the better question, how does palmitic acid raise it? The more one goes into the experimental technology required, the more complicated and difficult it becomes. Specialists in the field have been divided into two camps, those like Grundy and Ahrens (35), who found the increase of faecal bile acids (or neutral steroids) when saturated fats were replaced by polyunsaturated insufficient to account for the reduction in plasma cholesterol, and the others who find increased excretion themselves and argue that negative results have occurred mostly in patients with type II hyperlipidaemia, who have a special abnormality in cholesterol catabolism (36). Reduction of plasma triglycerides also occurs on polyunsaturated fat diets, and Lewis and Chait (37) have evidence that this may be due to decreased VLDL synthesis. Since VLDL is eventually converted into LDL, decreased synthesis may be an additional mechanism for the effect of polyunsaturated fats. This has been reported in the livers or experimental animals (38). A recent British report on priorities in nutrition research (39) includes among its recommendations: `It is important that the mechanism of action of the polyunsaturated acids should be elucidated ...' Recently, Grundy (40) reports clearly increased faecal bile acids and endogenous neutral steroids on polyunsaturated fat diets in patients with hypertriglyceridaemia. The foregoing is what happens in a metabolic unit, often with liquid formula diets and sometimes semi-synthetic fats. With natural foods and freeliving people, many other variables come into play. Correlations between dietary fatty acid pattern and plasma cholesterol can be considered at two levels correlation between groups of people of different cultures and correlations within a group of people having the same culture. Most of the differences between the mean plasma cholesterol of the different nations and ethnic groups in the world can be explained by differences in their consumption of dietary fats (41, 42). In a study of 9 different groups in southern Africa, we found the correlation between serum TG linoleic acid and plasma cholesterol was —0.34 (43). There are a small number of apparent exceptions. The best known are the Masai in East Africa. The young men of this tribe eat large amounts of milk and blood, but have plasma cholesterols averaging only 3.1 mmol/1 (120 mg/100 ml). Several observations have been put forward to explain this paradox. The Masai take a lot of exercise (44), they are lean and do not necessarily eat a high fat diet all the year round (45), they appear to have an efficient feedback mechanism for suppressing endogenous cholesterol synthesis on a high cholesterol intake (46) and the fat in fermented milk may have a different metabolic effect from butter fat as eaten, for example, in Europe (47). But when plasma cholesterols and dietary fat have been compared within a group of people who all have a similar way of life, significant correlations were not found (48, 49). To put these findings in perspective, there was no correlation either between the estimate of dietary iron and the haemoglobin levels in
Dietary Fat and Cholesterol Metabolism
57
the Framingham study (49). There are methodological weaknesses in the reported studies. For example, in Morris et al.'s (48) study of London bank men, there were varying intervals between the diet survey and taking blood, and 2 different cholesterol methods were used. In Framingham, the diet was estimated only from an interview intended to elicit usual intake (49) and then calculated from food tables. But even with better dietary measurements, weighing actual food consumed and analysing the foods for fatty acids, plasma cholesterol has not correlated with dietary fat (42). Repeat dietary measurements show that the variation of intake in the same individual is of the same magnitude as that between individuals (42). These dietary variations are too great for the small mean differences between individuals to show and it is known that on the same diet there are differences in plasma cholesterol between individuals, which must be constitutional. The only clear demonstration of correlation between dietary fat and plasma cholesterol was made in the members of an Antartic expedition; diet was measured 8 times and plasma cholesterol 12 times. The fat was mainly saturated and the correlation between fat calories and serum cholesterol was + 0.53 (50). Nevertheless, within a couple of weeks after starting a diet low in saturated fat and with increased polyunsaturated fat, people who have been on a usual European or North American diet will all show a fall of 10% or more in plasma cholesterol, which stays at the new, lower level as long as the therapeutic diet is continued, and for at least 8 years (51, 52). Only some cases of type lIA hyperlipidaemia are resistent. Note that those who start with higher cholesterols in a group stay higher than average in their group although they often show a greater absolute fall in plasma cholesterol (51).
Dietary Sterols and Plasma Cholesterol
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Different species of animals vary greatly in their response to dietary cholesterol. Massive hypercholesterolaemia is produced in rabbits fed cholesterol, while rats show little change unless they are given cholic acid as well, to inhibit the compensatory increase in bile acid production. For a long time, the effect in man was not clear. Keys et al. (53) maintained that dietary cholesterol had no effect and, as recently as 1969, a reputable textbook (54) was stating: `The dietary cholesterol has a negligible effect on plasma levels. Even eating ten eggs a day ... does not usually raise the level of plasma cholesterol.' With the accumulation of more experimental data, it is now accepted that exogenous cholesterol increases the plasma concentration (55). There are, however, three characteristics of the relationship. The effect is smaller than that of saturated fats; the response is non-linear, with the first 200-300 mg having a
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greater effect; thirdly, there is probably more individual variability than with dietary glycerides. Absorption of cholesterol is limited in man, from 50% at very low intakes, down to 10% at high intakes. Inefficiency and variability of absorption is one reason why plasma cholesterol only increases by small amounts; the other is that hepatic cholesterol synthesis is inhibited when plasma cholesterol tends to rise (56). However, the pools can accumulate 20 g of cholesterol in some subjects before the switch-off occurs (57). This feedback varies rather widely between different individuals (58) and possibly between different populations (46). In normal diets, there are sterols other than cholesterol. Sea foods usually contain 24-methylene-cholesterol as well. Plant lipids contain no cholesterol but a variety of phytosterols, such as ß-sitosterol (24-ethyl-cholesterol). We know most about the biological effects of this one. It lowers plasma cholesterol in man, mainly by competitive inhibition of absorption and reabsorption (57), but a small amount of phytosterols is absorbed (59) and may have systemic actions. Two rare cases have even been reported in which ß-sitοsterol accumulated in tendon xanthomas (60). ß-Sitosterol was marketed by Eli Lilly some years ago as a cholesterollowering agent under the trade name `Cytellín'. The dose is 3-6 g thrice daily (61, 62). The amounts in commercially refined vegetable oils are much smaller than this; the unsaponifiable fraction is usually under 1%. Of course, there are other dietary components that influence plasma cholesterol, particularly the energy (calorie) balance (63) some of the `dietary fibre' (64), possibly some saponíns (65), vitamin D (66), meal frequency (67), etc., but their effects are usually less than that of the dietary glycerides. Some Practical Implications
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(A) In working out a therapeutic diet for patients with hypercholesterolaemia, there are several unanswered questions: How important is dietary cholesterol? For example, liver contains 250300 mg cholesterol/100 g, compared with 500 mg in eggs, 100 mg in beef and 75 mg in chicken. Where should the line be drawn between allowing and forbidding? There is incomplete information about shellfish. Some advise that they should be avoided because of high cholesterol content, but the small amount of modern data show that the cholesterol is about the same as in meat, and in some shellfish an important proportion are other sterols, not well identified (68). Should peanuts and peanut butter be encouraged or discouraged? The arachidic and behenic acids they contain do not particularly raise the plasma cholesterol, but appear to be an atherogenic in animals (69, 70).
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How freely may egg whites be used? Could large amounts cause biotin deficiency? (B) What should be the ideal diet for the general population of Western countries, as one contribution to reducing the very high rates of CHD? In Finland, Norway, Sweden and the Medical Boards (71) recommend reduced fat intake, 25-35%, with an increased proportion of polyunsaturated fats. Also, more fruit and vegetables, etc. and more exercise. The Netherlands Nutrition Board (72) recommend that dietary total fat be reduced to about 33% of calories with linoleic acid increased to about 10-13% of calories. The British Department of Health Committee on Medical Aspects of Food Policy (73) agree that the fat intake of the general population should be reduced from the present 42% of calories, especially saturated fat, but do not recommend increasing polyunsaturated fat from the present 5% of calories. I am sure there is no single ideal diet. There are many good diets, which differ with a group's cultural traditions and the availability of foods. (There are also many bad diets.) There are, I believe rightly, still some reservations about the long-term safety of high intakes of polyunsaturated fats (74), which give more anxiety in some countries than others. These will be answered by more long-term research. All are agreed that saturated fats should be decreased. If people are not to lose weight they will have to replace these with either polyunsaturated oils, or starchy foods or mono-unsaturated fats like olive oil. There is very little CHD in the Southern Mediterranean, e.g. in Crete, where this is the main dietary fat (42, 75). Possibly the best would be a combination of the three. (C) These recommendations that are now being made will not be economically feasible unless they are integrated with agricultural policies and planning. Do we wish to see the egg industry run down and chicken production increased? Do we mean that butter should be replaced by either margarine rich in linoleic acid or made from the milk of cows fed with protected polyunsaturated fat? How can Europe produce enough polyunsaturated fat in its own fields to meet the demands of these recommendations? Should fish farming be encouraged and should this include shellfish? The food industry will be affected, and labelling regulations and people's food habits. It seems to me that we European nutritionists will soon have to consider the many practical implications of these recommendations about the ideal diet, as has been started in the USA (76) and in Australia (77). References
3
Cook, R.P. (ed.): Cholesterol, p. 174 (Academic Press, New York 1958). Goodman, D.S.: The measurement of cholesterol pools and turnover in man; in Jones Atherosclerosis. Proc. 2nd Int. Symp., pp. 242-248 (Springer, Berlin 1970). Smith, E.B. and Slater, R.S.: Relationship between plasma lipids and arterial tissue lipids. Nutr. Metabol. 15: 17-26 (1973). Downloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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4 5 6 7 8 9 10 11
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Truswell Scrimshaw, N.S. and Guzman, M.A.: Diet and atherosclerosis. Lab. Invest. 18: 623-628 (1968). Schwartz, C.J.; Stenhouse, N.S.; Taylor, Α.Ε. , and White, T.A.: Coronary disease severity at necropsy. Br. Heart J. 27: 731-739 (1965). Dayton, S.: Rationale for use of lipid-lowering drugs. Fed. Proc. Fed. Am. Socs exp. Biol. 30: 849-856 (1971). Gordon, T. and Kanne!, W.B.: Predisposition to atherosclerosis in the head, heart, and legs. J. Am. med. Ass. 221: 661--666 (1972). Greenhouse, A.H.: Blood lipids and strokes — are they related? J. chron. Dis. 23. 823-828 (1971). Armstrong, M.L.; Connor, W.E., and Warner, E.D.. Tissue cholesterol concentration in the hypercholesterolemic Rhesus monkey. Archs Path. 87: 87-92 (1969). Truswell, A.S.: Drugs and lipid metabolism. Proc. Nutr. Soc. 33: 215--224 (1974). Whitehead, T.P.; Browning, D.M., and Gregory, A.: A comparative survey of the results of analyses of blood serum in clinical chemistry laboratories in the United Kingdom. J. clin. Path. 26: 435-445 (1973). Schwartz, M.K. and Hill, P.: Problems in the interpretation of serum cholesterol values. Prey. Med. 1: 167--177 (1972). Keys, A. and Fidanza, F.: Serum cholesterol and relative body weight of coronary patients in different populations. Circulation 22: 1091-1106 (1960). Arvidson, G. and Malmros, H.: Studies on the influence of dietary fat on the fatty acid composition of serum lipids on humans. Z. ErnahrWiss. 11: 105-119 (1972). Paulsrud, J.R.; Pensler, L.; Whitten, CF; Stewart, S., and Holman, R.T.: Essential fatty acid deficiency in infants induced by fat-free intravenous feeding. Am. J. clin. Nutr. 25: 897-904 (1972). Franzini, C. and Schivi, T.: On the distribution of serum cholesterol between o- and ß-lipoproteins. Clin. chim. Acta 9: 87-89 (1964). Brunte-Stewart, B.; Antonis, A.; Eales, L., and Brock, J.F.: Effects of feeding different fats on serum cholesterol level. Lancet i: 521-526 (1956). Truswell, A.S., Hansen, J.D.L.; Watson, CE., and Wannenburg, P.: Relation of serum lipids and lipoproteins to fatty liver in kwashiorkor. Am. J. clin. Nutr. 22: 568 -576 (1969). Lewis, L.A.; Zuehlke, V.; Nakamoto, S.; Kolff, W.J., and Page, I.H.: Renal regulation of serum ‚s-lipoproteins. Decrease of α-lipoproteins in the absence of renal function. New Engl. J. Med. 275: 1097-1100 (1966). Carlson, L.A. and Kolmodin-Hedman, B.: Hyper-o-lipoproteinemia in men exposed to chlorinated hydrocarbon pesticides. Acta med. scand. 192: 29-32 (1972). Miller, G.J. and Miller, Ν.Ε. : Plasma-high-density lipoprotein concentration and development in ischaemic heart disease. Lancet i: 16-19 (1975). Hollister, L.Ε. and Wright, A.: Diurnal variation of serum lipids. J. Atheroscler. Res. 5. 445-450 (1956). Friedewald, W.T.; Levy, R.I., and Fredrickson, D.S.: Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin. Chem. 18: 499-502 (1972). Fredrickson, D.S.: Plasma lipoproteins and apolipoproteins. Harvey Lect. 68: 185-237 (1974). De Langen, C.D.: Cholesterike-stoffwisselrng en rassenpathologie. Geneesk Tijdschrift Nederl-Indie 26: 1-34 (1916). Keys, A.: Human atherosclerosis and the diet. Circulation 5: 115-118 (1952). Kinsell, L. W.; Partridge, J.; Boling, L.; Margen, S., and Michaels, G.: Dietary modificaDownloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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tun of serum cholesterol and phospholipid levels. J. clan. Endocr. 12: 909-913 (1952). 28a Grande, F.; Anderson, J. T., and Keys, Α.: Comparison of effects of palmitic and stearic acids in the diet on serum cholesterol in man. Am. J. clin. Nutr. 23: 1184-1193 (1970). 28b Grande, F.; Anderson, J.T., and Keys, Α.: Diets of different fatty acid composition producing identical serum cholesterol levels in man. Am. J. clin. Nutr. 25: 53-60 (1972). 29 Hegsted, D.M.; McGandy, R.B.; Myers, M.L., and Stare, F.J.: Quantitative effects of dietary fat on serum cholesterol in man. Am. J. clin. Nutr. 17: 281-295 (1965). 30 McGandy, R.B.; Hegsted, D.M., and Myers, M.L.: Use of semisynthetic fats in determining effects of specific dietary fatty acids on serum lipids in man. Am. J. clin. Nutr. 23: 1288-1298 (1970). 31 Vergroesen, A.J. and De Boer, J.: Effecten van meervoudig onverzadigde en andere vetzuren in de voeding. Voeding 32: 278-290 (1971). 32 Anderson, J.T.; Grande, F., and Keys, Α.: Hydrogenated fats in the diet and lipids in the serum of man. J. Nutr. 75: 388-394 (1961). 33 Vergroesen, A.J.: Dietary fat and cardiovascular disease: possible modes of action of linoleic acid. Proc. Nutr. Soc. 31: 323-329 (1972). 34 Mattson, F.H.; Hollenbach, E.J., and Kligman, Α.M.: Effect of hydrogenated fat on the plasma cholesterol and triglyceride levels of man. Am. J. clin. Nutr. 28: 726-731 (1975). 35 Grundy, S.M. and Ahrens, E.H., jr.: The effects of unsaturated dietary fats on absorption, excretion, synthesis and distribution of cholesterol in man. J. clin. Invest. 49: 1135-1152 (1970). 36 Connor, W.E.: The effects of dietary lipid and sterols on the sterol balance; in Jones Atherosclerosis, Proc. 2nd Int. Symp., pp. 253-261 (Springer, Berlin 1970). 37 Lewis, B.: Personal commun. (1975). 38 Bartley, J. and Abraham, S.: Effect of dietary fats of different fatty acid composition on hepatic lipogenesis in rats and mice. 9th Int. Congr. Nutrition, Mexico 1972, abstr., p. 67. 39 Agricultural Research Council/Medical Research Council: Food and Nutrition Research. Report of the ARC/MRC Committee, p. 130 (HMSO, London 1974). 40 Grundy, S.M.: Effects of polyunsaturated fats on lipid metabolism in patients with hyperlipidemia. J. clin. Invest. 55: 269-282 (1975). 41 Gordon, H.: The regulation of the human serum cholesterol. Postgrad. med. J. 35: 186-196 (1959). 42 Keys, A. (ed.): Coronary heart disease in seven countries. Circulation 41: suppl. 1, pp. 1-211 (1970). 43 Truswell, A.S. and Mann, J.1.: Epidemiology of serum lipids in southern Africa. Atherosclerosis 16: 15-29 (1972). 44 Mann, C. V.; Shaffer, R.D., and Rich, A.: Physical fitness and immunity to heartdisease in Masai. Lancet íi: 1308-1310 (1965). 45 Shaper, A.G.: Cardiovascular disease in the tropics. IV. Coronary Heart Disease. Br. med. J. iv: 32-35 (1972). 46 Ho, K.J.; Biss, K.; Mikkelson, B.; Lewis, L.A., and Taylor, CB.: The Masai of East Africa: some unique biological characteristics. Archs Path. 91: 387-410 (1971). 47 Mann, G. V. and Spoerry, A.: Studies of a surfactant and cholesteremia in the Masai. Am. J. clin. Nutr. 27: 464-469 (1974). 48 Morris, J.N.; Marr, J.W.; Heady, J.A.; Mills, G.L., and Pilkington, T.R.E.: Diet and plasma cholesterol in 99 bank men. Br. med. J. i: 571-576 (1963).
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Kannel, W.B. and Gordon, T.: The Framingham Study. An epidemiological investigatun of cardiovascular disease; sect. 24. The Framingham diet study: diet and the regulation of serum cholesterol (US Government Printing Office, Washington 1970). 50 Easty, D.L.: The relationship of diet to serum cholesterol levels in young men in Antartica. Br. J. Nutr. 24: 307-312 (1970). 51 Leren, P.: The effect of plasma cholesterol-lowering diet in male survivors of myocardial infarction. Acta med. scand. Suppl. 466: 1-92 (1966). 52 Dayton, S.; Pearce, M.L.; Hashimoto, S.; Dixon, W.J., and Tomiyasu, U.: A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 39/40: suppl. II, pp. 1-62 (1969). 53 Keys, Α.; Anderson, J.T.; Mickelson, O.; Adelson, S.F., and Fidanza, F.: Diet and serum cholesterol in man: lack of effect of dietary cholesterol. J. Nutr. 59: 39-56 (1956). 54 Davidson, S. and Passmore, R.: Human nutrition and dietetics; 4th ed., p. 102 (Livingstone, Edinburgh 1969). 55 Keys, A.; Grande, F., and Anderson, J.T.: Bias and misrepresentation revisited: perspective on saturated fat. Am. J. clin. Nutr. 27: 188-212 (1974). 56 Dietschy, J.M. and Wilson, J.D.: Regulation of cholesterol metabolism. New Engl. J. Med. 282: 1128-1138, 1179-1185, 1241-1249 (1970). 57 Grundy, S.M.; Ahrens, E.H., jr., and Davignon, J.: The interaction of cholesterol absorption and cholesterol synthesis in man. J. Lipid Res. 10: 304-315 (1969). 58 Quintdo, E.; Grundy, S.M., and Ahrens, E.H., jr.: Effects of dietary cholesterol in the regulation of total body cholesterol in man. J. Lipid Res. 12: 233-247 (1971). 59 Ravi Subbiah, M.T.: Dietary plant sterols — current status in human and animal sterol metabolism. Am. J. clin. Nutr. 26: 219-225 (1973). 60 Bhattacharyya, A.K. and Connor, W.E.: β-Sitοsterolemia and xanthomatosis: a newly described lipid storage disease in two sisters. J. clin. Invest. 52: 9A (1973). 61 Best, M.M.; Duncan, C.H.; Loon, E.J. Van, and Wathen, J.D.: The effects of sitosterol on serum lipids. Am. J. Med. 19: 61-70 (1955). 62 Farquhar, J. W. and Sokolow, M.: Response of serum lipids and lipoproteins of man to beta sitosterol and safflower oil. A long-term study. Circulation 17: 890-899 (1958). 63 Pincherle, G.: Factors affecting the mean serum cholesterol. J. chron. Dis. 24: 289297 (1971). 64 Trustyell, A.S. and Kay, R.M.: Absence of effect of bran on blood lipids. Lancet i: 922-923 (1975). 65 Birk, Y.: Saponins; in Liener Toxic constituents of plant foodstuffs, pp. 169-210 (Academic Press, New York 1969). 66 Linden, V.: Vitamin D and myocardial infarction. Br. med. J. iii: 647-650 (1974). 67 Gwinup, G.; Byron, R C.; Roush, W.H.; Kruger, F.A., and Harnwj, G.J.: Effect of nibbling versus gorging on serum lipids in man. Am. J. clin. Nutr. 13: 209-213 (1963). 68 Feeley, R.M.; Criner, P.E., and Watt, B.K.: Cholesterol content of foods. J. Am. diet. Ass. 61: 134-149 (1972). 69 Howard, A.N. and Gresham, G.A.: Dietary aspects of atherosclerosis and thrombosis. Int. Z. VitamForsch. 38: 545-559 (1968). 70 Kritchevsky, D.; Tepper, S.A.; Vesselinovitch, D., and Wissler, R. W.: Cholesterol vehicle in experimental atherosclerosis. 13. Randomized peanut oil. Atherosclerosis 17: 225-243 (1973). 71 Combined Medical Boards of Finland, Norway and Sweden: Medicinsky synpunkter på folkkosten i de nordiska landerna (1969); quoted by Davidson, Passmore, Brock and Downloaded by: Université René Descartes Paris 5 193.51.85.197 - 12/15/2019 3:17:58 PM
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Truswell Human nutrition and dietetics; 6th ed., p. 652 (Churchill/Livingstone, Edinburgh/London 1975). 72 Voedingsraad: Advies over hoeveelheid en/of aard der vetten in de voeding. Volksgesondheid 25, Ministerie van Volksgesondheid en Milieuhygiene (Staatsuitgeverij, 's-Gravenhage 1973). 73 Department of Health and Social Security: Diet and coronary heart disease. Report of the Advisory Panel of the Committee on Medical Aspects of Food Policy (Nutrition). Report on health and social subjects, vol. 7 (HMSO, London 1974). 74 Truswell, A.S.: Fats and fatty oils: nutritional and medical aspects. Reports on the progress of applied chemistry during 1973, vol. 58, pp. 459-470 (Academic Press, New York 1975). 75 Christakis, G.; Severinghaus, E.L.; Maldonado, Z.; Kafatos, F.C., and Hashím, S.A.: Crete: a study in the metabolic epidemiology of coronary heart disease. Am. J. Cardiol. 15: 320-332 (1965). 76 Symposium: Developing foods for the cardiac-concerned. Food Technol. 1974: 16-32. 77 Food, fats and heart disease: Conf. on Changing Food Habits. Food Technol. Aust. 26: Suppl. 9, pp. 385-431 (1974).
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Prof. Dr. A.S. Truswell, Department of Nutrition, Queen Elizabeth College, University of London, Campden Hill, London W8 7ΑΗ (England)
