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HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



treated with estrogen daily, showed appreciable lower- 

 ing of their serum cholesterol levels without a sig- 

 nificant effect on their death rate, compared with a 

 comparable untreated control group. The apparent 

 lack of protection may have been related to the choice 

 of subjects who already had experienced myocardial 

 infarction. 



Dietary Fatty Acids 



It is now established that diet can have a profound 

 influence on serum lipids; indeed, the relation of diet 

 to serum lipids has been under intensive study in 

 recent years. More information is available concern- 

 ing the influence of dietary fat on serum lipids than 

 about the effect on serum lipids of other dietary con- 

 stituents. Not long ago, it was believed that the total 

 quantity of fat in the diet was the major factor affect- 

 ing serum lipids (117). In particular, the American 

 diet providing 40 to 45 per cent of its calories as fat 

 was implicated as being responsible for the relatively 

 high serum cholesterol values observed in adults in 

 the United States. It is now clear that the "quality" 

 of the fat in the diet is of primary importance in 

 determining the response of the serum cholesterol 

 fraction, although the relative proportions of carbo- 

 hydrate and fat in the diet appear to influence the 

 serum triglyceride concentration. It is of interest to 

 review briefly some of the events that have led to 

 these conclusions. 



In 1933 Schoenheimer (183) reported that feeding 

 a wholly vegetarian diet to a patient with hyper- 

 cholesteremia resulted in marked lowering of serum 

 cholesterol. During the ensuing two decades, rela- 

 tively little further information of this kind was gath- 

 ered. Extensive studies regarding the metabolism of 

 cholesterol and other lipids were undertaken during 

 this time and significant discoveries were made. It was 

 found that cholesterol is readily synthesized in the 

 body from small carbon fragments (171), and that 

 the major catabolic pathway for cholesterol involves 

 conversion to bile acids (26). 



In 1952, Groen and associates (87) demonstrated 

 by means of well-controlled and prolonged experi- 

 ments that substitution of vegetable for animal fats 

 in the diet can lower serum cholesterol in man, even 

 if the total fat content remains unchanged. During 

 the same year Kinsell and associates (122) reported 

 that ingestion of diets containing relatively large 

 amounts of vegetable fat consistently resulted in a 

 significant fall in the level of serum cholesterol and 



phospholipids in human subjects. These observations 

 have been amply confirmed (2, 3, 22, 36, 123, 140). 



It soon became apparent that the fatty acid com- 

 position of dietary fat was of primary importance in 

 determining serum cholesterol response. The experi- 

 ments in which vegetable oils were used stimulated 

 interest in the possible role of the essential fatty acids. 

 Subsequently, Kinsell and associates (124) concluded 

 that the major cholesterol-lowering ingredient in 

 various vegetable fats was, in fact, linoleic acid. Then, 

 in a series of well-controlled comparative experiments 

 in man, utilizing formula diets deriving 40 per cent of 

 their calories from fat, Ahrens et at. (4) observed that 

 the effects on serum cholesterol of various edible fats 

 could be related to their iodine value. Thus, fats with 

 high iodine values such as safflower, corn, and cotton- 

 seed oils proved to be relatively hypocholesteremic, 

 while fats with low iodine values such as palm oil, 

 beef, butter, cocoa butter, and coconut oil tended to 

 raise the serum cholesterol level. Intermediate or 

 neutral effects on serum cholesterol were obtained 

 with fats with intermediate iodine values such as 

 peanut and olive oils. In a later study (5) the Rocke- 

 feller group found that menhaden oil, a fat virtually 

 free of linoleic acid and yet with an extremely high 

 iodine value (I, number 180) was at least as effective 

 as corn oil in lowering serum cholesterol. Keys and 

 associates (120) have proposed a formula designed to 

 predict the effect of a given pattern of dietary fatty 

 acids on serum cholesterol in man. The formula at- 

 tempts to take into account the different roles of the 

 saturated, monounsaturated, and polyunsaturated 

 fatty acids in the diet; however, it remains to be 

 demonstrated that such an analysis can be applied 

 successfully in a variety of dietary situations (4). 



In any event, it is clear that serum levels of choles- 

 terol and low-density lipoproteins can be changed 

 significantly when the pattern of fatty acids in the 

 diet is rearranged. When the glycerides of a dietary 

 fat contain predominantly saturated long-chain fatty 

 acids, concentrations of serum total cholesterol and 

 certain low-density lipoproteins tend to rise. When 

 such dietary glycerides contain an appreciable pro- 

 portion of polyunsaturated fatty acids (whether essen- 

 tial or not), serum cholesterol, and low-density lipo- 

 proteins tend to decrease. The degree of change in 

 serum lipids seems to depend upon the magnitude 

 of change in the pattern of the fatty acids in the diet. 

 Thus, it may be necessary to double or triple the 

 polyunsaturated fatty acid content of the diet (with- 

 out change in the total fat intake) to induce an appre- 

 ciable lowering of serum cholesterol. However, even 



