LIPID METABOLISM 



U87 



acid metabolism (100); however, the exact mecha- 

 nism remains to be clarified. Studies of (/-thyroxine 

 in man revealed no reliable dose-response of serum 

 cholesterol over a 6-month period, nor was there a 

 dose which would be effective in lowering serum 

 cholesterol without provoking angina (151 ). 



Neomycin has been reported to lower serum 

 cholesterol and simultaneously to increase fecal ex- 

 cretion of bile acids (81, 82, 181). The influence of 

 neomycin on bile acid metabolism may be related 

 to its profound effect on intestinal flora and the 

 possible damage it inflicts on the villi of the intestinal 

 mucosa. 



4) Increased tissue removal of cholesterol. It is 

 suspected that the estrogenic hormones and their 

 congeners (12, 34) may lower serum cholesterol 

 by increasing the activity of the reticuloendothe- 

 lial system and thereby accelerating the removal 

 of cholesterol-rich lipoproteins from the plasma. 

 Whether cholesterol catabolism is further enhanced 

 within the reticuloendothelial system remains un- 

 known. The effect of estrogens on cholesterol bio- 

 synthesis also is not clear; however, there is evidence 

 that estrogen administration is not associated with 

 an increased rate of bile acid excretion. A variety of 



teals 



fig. 8. Mechanisms for lowering plasma cholesterol. 

 / : Inhibition of cholesterol biosynthesis (triparanol). 2: 

 Inhibition of cholesterol absorption (sitosterols). 3: Promotion 

 of cholesterol degradation — a, polyunsaturated fatty acids; 

 b, bile acid sequestrants. 4: Increased tissue removal of 

 cholesterol (estrogens). (From Bergen & Van Itallie, Ann. 

 Internal Med. In press.) 



other substances (63, 166) too numerous to discuss 

 in detail also are capable of inducing a reduction in 

 serum cholesterol. The four mechanisms for lowering 

 cholesterol that have been described are summarized 

 in figure 8. 



BLOOD LIPIDS AND ATHEROSCLEROSIS 



Virtually no information based on direct observa- 

 tion is available concerning the relationship in man 

 between circulating lipids and atherosclerosis. The 

 difficulty has been that the tools for diagnosing occult 

 atherosclerosis are inadequate. There is indirect evi- 

 dence — epidemiologic, experimental, clinical, and 

 pathologic — that sustained elevation of the plasma 

 low-density lipoproteins is associated with an in- 

 creased rate of atheroma formation. It is suspected 

 that plasma lipoprotein may be '"filtered" through 

 intimal cells under arterial pressure and that accumu- 

 lation of lipid in the subintimal area is accelerated by 

 continued traffic of plasma rich in "unstable" lipo- 

 protein through the arterial wall (153, 201). 



Animal experiments have shown that when an 

 increased plasma concentration of ^-lipoproteins is 

 achieved by dietary or other means, atherosclerosis 

 usually results (64, 143, 211). The early vascular 

 changes observed in experimental atherosclerosis are 

 believed by many observers to have a close resem- 

 blance to early human lesions. 



Evidence is also available from studies in man that 

 prolonged elevation of the serum cholesterol is asso- 

 ciated with an increased susceptibility to athero- 

 sclerosis and its clinical manifestations. In diseases 

 such as diabetes and hypothyroidism in which serum 

 lipids tend to be elevated, the incidence of athero- 

 sclerosis also is increased. Moreover, patients with 

 angina pectoris or a history of myocardial infarction 

 tend to have serum lipid levels higher than those of 

 apparently healthy control subjects. This difference 

 in lipid levels is most striking when groups below the 

 age of 45 are compared (201). 



Epidemiologic studies of populations in various 

 parts of the world (18) involving correlation of serum 

 cholesterol levels with prevalence of clinically mani- 

 fest atherosclerosis and presence of the disease at 

 autopsy have given additional support to the pro- 

 posed relationship between hypercholesteremia and 

 atherosclerosis. Most epidemiologic studies attempt- 

 ing to relate coronary heart disease to levels of serum 

 cholesterol are retrospective in that the subjects 

 studied have already exhibited clinical manifesta- 

 tions of atherosclerotic heart disease. The Framing- 



