( Originally Published 1956 )
UNTIL recently, few attempts have been made to evaluate lipid nutrition aside from estimation of the extent of body fat stores in relation to obesity. Fats have been considered largely as a source of calories, as carriers of the fat soluble vitamins and as contributors to the palatability and satiety value of diets. There has been considerable but sporadic interest in cholesterol metabolism and hypercholesterolemic states. A few studies have been carried out relative to the essentiality for man of certain polyunsaturated fatty acids which are known to be required in the diet of many animal species. In the past few years, however, evidence has accumulated that suggests a relationship between dietary fat, serum lipid levels and the development of atherosclerosis. As a result, extensive research in lipid metabolism has been stimulated and a new area of nutritional diagnosis is being developed.
Lipids comprise a wide variety of chemical compounds the most important of which are fatty acids, triglycerides (neutral fat), phospholipids and sterols. Triglycerides consist of three fatty acids combined with glycerol. There are many types of phospholipids and there are two important sterols; cholesterol, found in animal tissues and sitosterol, in plants.
Fatty acids differ in chain length (number of carbon atoms) and in degree of unsaturation (number of double bonds). The polyunsaturated fatty acids, linoleic, linolenic and arachidonic constitute the essential fatty acids for animals. Presumably they will be found to be essential for man but this has not been demonstrated unequivocally.
The optimal level of fat in the diet is not known and since fat may be formed from protein or carbohydrate, no requirement can be formulated. Recent evidence suggests that both the amount and type of fat in the diet have an important effect on serum lipid levels and that lipid levels in turn may have an influence on the development of atherosclerosis. Diets high in fat increase serum cholesterol and other lipid levels if other conditions re-main the same. With diets of comparable fat content, serum cholesterol concentrations are lower when the dietary fat contains large amounts of unsaturated fatty acids than when it is made up largely of saturated fatty acids. The polyunsaturated or "essential" fatty acids may be of particular importance in this situation. Thus, in evaluating lipid nutrition not only should the total fat intake be ascertained but also the type of fatty acids included in the diet.
The cholesterol content of the diet does not significantly influence serum cholesterol concentration over a range of intake of 250 to 800 mg. daily which corresponds to quantities present in a wide variety of diets (53). Cholesterol is manufactured in amounts of 1.5 to 2.0 gm. daily from acetate (54) which in turn can be formed from protein or carbohydrate.
SERUM LIPID CONCENTRATIONS
Plasma contains approximately 300 mg. of fatty acids per 100 ml.; 80 per cent of the fatty acids are present as phospholipids or as simple esters of glycerol (triglycerides ), 15 per cent are esterified with cholesterol and 5 per cent are unesterifled. The blood cholesterol level varies widely among population groups and among individuals and increases with age, but neither the normal nor optimal level is known. In this country, Stare has reported mean cholesterol levels in men and women aged 40-45 years to be 240 and 225 mg. per 100 ml. respectively. There is some evidence that suggests that these levels may be higher than desirable. Sixty per cent or more of the cholesterol in blood is esterified, the remainder being present in free form. It is thought that esterification occurs preferentially with unsaturated fatty acids.
All of the lipids in blood are transported in combination with protein; cholesterol, phospholipid and triglyceride with globulin, unesterified fatty acids with albumin. Lipoproteins have been studied with several techniques to effect separation, e.g., by electrophoresis, ultracentrifugation and Cohn fractionation. Accordingly, the major fractions have been designated variously, leading to con-fusion in terminology (51b). When lipoproteins are separated by ultracentrifugation, the very low density lipoproteins with Svedberg flotation (Si) unit values of 10 to 400, correspond in general to the "alpha2" lipoproteins separated electrophoretically; lipoproteins of low density, S f values of 0 to 10, correspond to the "beta" lipoproteins, while the high density lipoproteins include the "alpha" lipoproteins. The albumin-unesterified fatty acid complex is of still higher density. Chylomicrons, which are present only when Iarge amounts of absorbed fat has entered the blood, have extremely low density, St value about 40,000 units. Both high and low density lipoproteins contain protein, triglyceride, cholesterol and phospholipid but in varying proportions.
It is possible to measure the several moieties which make up the various groups of lipoproteins including their constituent fatty acids. Methods are difficult, however, and applicable largely in research rather in general diagnosis.
Little is known about the specific functions of the lipoproteins or relationships of one class to another. Frederickson (51b) has stated "It appears that the unifying hypothesis of a single parent molecule, such as the chylomicron, which would simply be shorn of more and more of its triglyceride to become lipoproteins of successively decreasing size and greater density is not tenable for the whole lipoprotein spectrum although it may be true in part."
Studies of the mechanism by which blood is cleared of fat indicate that a lipoprotein lipase probably catalyzes the hydrolysis of triglyceride and is responsible for the disappearance of chylomicrons and very low density lipoproteins. This enzyme has been isolated from the heart and from adipose tissue. It appears to be identical with the "clearing factor" found in blood after the injection of heparin.
There is evidence that the unesterified fatty acid fraction of plasma is of considerable significance; presumably it is in this form that fat is transported from depots to other tissues for utilization.
In view of the complexities of lipid metabolism, it is obvious that evaluation of lipid nutrition will be no easy task. A relatively simple biochemical measurement, that of serum cholesterol, has been widely studied in recent years, particularly with reference to atherosclerosis. The current status of knowledge of relationships between dietary fat, serum lipid levels and atherosclerosis has been summarized in several recent reviews.
Determination of serum cholesterol concentration is of value in assessment of lipid nutrition although the normal or ideal level is unknown and there are wide variations among individuals and even in the same person at different times. The incidence of atherosclerosis is increased in diseases associated with hypercholesterolemia such as diabetes mellitus, hypothyroidism and the nephroses. Per-sons who have coronary artery disease have been found to have higher mean levels of serum cholesterol than persons of similar age and sex who have no clinically demonstrable atherosclerosis. In spite of the limitations in interpreting serum cholesterol concentration, this measurement gives as much information relative to the possibility of atherosclerotic complications developing as does any other determination currently available.
Simple examination of fasting serum for turbidity or milkiness, in conjunction with a cholesterol determination, is also informative. In general, an elevated serum cholesterol level will be associated with an increase in the concentration of low or very low density lipoproteins. Marked elevation of cholesterol concentration in clear serum usually reflects an increase in the low density lipoproteins (Sr 0 to 10) and the serum often is deep yellow in color due to the carotene carried by this fraction. Lactescence of the serum implies an increase in triglycerides and of the lower density (higher Sr) lipoproteins. Idiopathic hyperlipemia is associated with marked turbidity and the bulk of the triglyceride-rich lipoproteins may be chylomicrons.
Measurement of specific lipoprotein fractions is of assistance in evaluating lipid metabolism in a number of diseases. Xanthomatous biliary cirrhosis may be accompanied by very low concentrations of high density lipoproteins even though serum cholesterol may be abnormally high. In untreated diabetic acidosis and glycogen storage disease, the low density lipoproteins are increased. In the nephrotic syndrome, the concentration of very low density lipoproteins is often elevated. There is a difference in lipoprotein concentrations between men and women.
In the age group 15 to 65, the male has higher concentrations of all major low density lipoproteins than the female. Gofman has shown that in patients who have had a myocardial infarction, the levels of low density lipoproteins, especially St 12-400 classes, are elevated.
Other measurements of lipid nutrition include chylomicron counts and determination of phospholipid concentration in blood and of the phospholipid-cholesterol ratio. Accurate chylomicron counts are difficult to obtain and the interpretation of findings is uncertain. Elevated or prolonged chylomicronemia has been suggested as a possible contributing factor to the development of ather-osclerosis but data are few. The normal phospholipid concentration in serum is in the neighborhood of 220 mg. per 100 ml. and increases with age as does cholesterol concentration. A decrease in the phospholipid-cholesterol ratio has been considered an undesirable finding. The concentration of polyunsaturated fatty acids in serum may be measured but methods are difficult and as yet no standards of normalcy are available. It is anticipated that the great attention currently being directed to lipid metabolism will evolve new tests and more accurate methods of evaluating lipid nutrition in the near future.