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HANDBOOK OF PHYSIOLOGY 



CIRCULATION' II 



Cholesterol esterifies readily with polyunsaturated 

 fatty acids such as linoleic acid (115). When the die- 

 tary fatty acids are predominantly saturated, esters 

 such as cholesteryl oleate and palmitate are likely to 

 occur in increasing amounts and, conceivably, may 

 be less available for excretion and conversion to bile 

 acids bv the liver. 



Additional Influences on Serum Lipids 



Other dietary manipulations also can influence 

 serum lipids (63, 153, 166). A drastic decrease in 

 dietary intake of protein is associated with lowering 

 of serum total cholesterol (and fi-lipoproteins) in 

 man (76, 152). High protein intakes above 10 per 

 cent of total daily calories have been found to be 

 effective in lowering serum cholesterol and /3-lipo- 

 proteins in animals but not in man (153). A sub- 

 stantial decrease in the proportion of fat in the diet 

 may be associated with a lowering of serum choles- 

 terol, but in certain individuals a considerable rise in 

 serum triglycerides may occur (4, 6). Such diets 

 usually contain a large quantity of carbohydrate, 

 much of which gets converted by the body into fat. 



There is evidence from studies in laboratory animals 

 and human subjects that the type of carbohydrate in 

 the diet can affect serum lipids. Compared to sucrose, 

 starch promotes bile acid excretion and tends to 

 lower serum cholesterol in the rat (165). It has also 

 been reported that when the carbohydrates of 

 legumes are substituted isocalorically for sucrose in 

 the diets of human subjects, cholesterol levels are 

 reduced to a slight degree (9). 



The effect of a given diet on caloric balance must 

 also be taken into account. Patients in negative 

 caloric balance can often have a transient decrease in 

 serum lipids on this basis; on the other hand, during 

 active weight gain, serum lipids tend to rise (142, 

 204). Weight reduction may induce a decline in 

 serum lipids in persons with hyperlipidemia. It is 

 not certain whether such a decrease occurs only while 

 weight actuallv is being lost or whether, in some in- 

 stances, the improvement in serum lipids will be sus- 

 tained for as long as weight is maintained at a reduced 

 level. However, as was mentioned earlier, during a 

 sustained fast the serum levels of the low-density 

 lipoproteins tend to increase; this contrasts with the 

 decline in serum lipids shown bv nonfasting patients 

 in negative caloric balance. 



Pharmacologic approaches to lowering serum 

 cholesterol have included use of agents with the fol- 

 lowing mechanisms of action : 



/) Inhibition of cholesterol biosynthesis. Under 



this category are included triparanol (138, 193), 

 benzmalecene (15), and possibly nicotinic acid (7, 82, 

 158). Agents which inhibit cholesterol biosynthesis 

 also may interfere with other important synthetic 

 processes such as steroid biogenesis; hence, they are 

 potentially toxic for man. 



_') Inhibition of cholesterol absorption from the 

 gastrointestinal tract. Plant sterols such as sitosterol 

 have been used for this purpose in man (20, 188). The 

 mechanism for inhibition of cholesterol absorption 

 remains to be demonstrated. Moreover, the effective- 

 ness of sitosterol in lowering serum cholesterol in man 

 has been questioned. Studies by Levere and his asso- 

 ciates (131) suggested that no decrease in serum 

 cholesterol could be attributed confidently to sitos- 

 terol administration, and that any apparent decrease 

 might be caused by great fluctuations in serum choles- 

 terol observed in such studies in man. 



3) Promotion of cholesterol degradation. Reference 

 already has been made to the polyunsaturated fatty 

 acids and the possibility that they might act by pro- 

 moting the rate of cholesterol breakdown to bile 

 acids. Simple addition to the diet of relatively small 

 quantities of polyunsaturated fatty acids cannot be 

 relied upon to induce significant lowering of the 

 serum cholesterol level (159). Pharmaceutical prepa- 

 rations containing linoleic acid and sometimes sup- 

 plemented with small quantities of pyridoxine and 

 tocopherol offer no advantage over the various 

 linoleate-rich oils such as corn and cottonseed that 

 can be purchased inexpensively at the grocery. 

 Moreover, as mentioned earlier, the polyunsaturated 

 fatty acids, in order to be effective in lowering serum 

 cholesterol, must be consumed in relatively large 

 amounts and their intake integrated with an over-all 

 reduction in the consumption of saturated fatty acids 

 as part of a carefully adhered-to regimen. 



An interesting group of substances has been found 

 capable of lowering serum cholesterol by binding bile 

 acids in the gut and thereby promoting their fecal 

 excretion. These are the anion exchange resins (14, 

 196, 202) that form nonabsorbable complexes with 

 bile acids. Appropriately, they have been termed 

 "bile acid sequestrants" and of these cholestyramine 

 has been studied extensively in man. Cholestyramine 

 is apparently innocuous since it does not seem to enter 

 the body. Long-term effects of bile acid sequestration 

 in man are at present unknown. The net effect of the 

 bile acid sequestrants appears to be similar to that of 

 the polyunsaturated fatty acids; namely, promotion 

 of cholesterol degradation. 



Thyroid hormones and their analogues ([]^, 77, 151) 

 may lower cholesterol bv virtue of an effect on bile 



