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LIPIDS. Lipids (fats and oils) have borne the brunt of the blame for the degenerative diseases (heart disease and cancer) that are the major causes of death in the developed world. The negative view of lipids has obscured their essentiality for human health. If a problem exists, it is one of quantity, in general, and specific lipids in particular.

Lipids are important for maintenance of human health and well-being in a number of ways. Probably the most important function of lipids is provision of an efficient energy source. Fat provides 9 calories of energy per gram or 2.25 times as much as either carbohydrate or protein. Carbohydrate is not stored in the body and protein stores are predominantly muscle, whose breakdown entails serious health consequences. Fat is stored as such and can be easily mobilized if needed. In primitive times survival may have been possible because of energy provided by metabolic use of stored fat (Gurr and Harwood, 1991).

Lipids are a group of substances of diverse structures that share the common trait of being soluble in solvents such as ether or benzene. The major lipids of the body are triglycerides, which comprise a molecule of glycerol to which three fatty acids are bonded. Phospholipids are substances in which glycerol carries only two fatty acids plus phosphoric acid and an organic base such as choline or serine. Cholesterol is a member of the family of large complex molecules generically called steroids. It has the capacity to carry one molecule of fatty acids (cholesteryl ester). Cell membranes are predominantly composed of phospholipids and cholesterol. Cell membranes confer stability to cells and control entry or release of chemicals into or from the cell. Lipids serve as effective insulators and help in maintaining body temperature. Important organs such as the heart, kidneys, and reproductive organs are cushioned by fat. Nerves are protected by a sheath (myelin) that contains cholesterol, phospholipids, and other lipids.The animal organism carries a number of essential substances that catalyze chemical reactions in cells. These are called vitamins and are designated by letters. The B and C vitamins are soluble in water; the others, vitamins A, D, E, and K, are insoluble in water but soluble in fats. They are transported in lipids in the blood and stored in fat in the body.

Chemistry

Cholesterol is a molecule that is found in the membrane of every cell. About 0.2 percent of the average body weight is cholesterol. Most of this cholesterol is present in the muscle (cell membrane) or brain (as insulation against trauma). The functions of cholesterol in the brain are still poorly understood. Most of the cholesterol in the body is manufactured in the liver, and the diet makes a relatively small contribution to this pool. Cholesterol, in turn, is the parent substance of a number of vital compounds. Among these are the bile acids that are necessary for proper absorption and digestion of fat; the corticosteroids such as cortisol and hydrocortisone that are essential to life; progesterone which is required for normal reproduction, and the male and female sex hormones. The involvement of cholesterol in the etiology of coronary heart disease will be discussed below.

Fatty acids are chains of carbon acids that culminate in an acidic group called a carboxyl group. Each carbon atom has the capacity to bind four other atoms. In the fatty acid chain, two of those binding elements are bound to the carbon atoms on either side, and the other two are bound to hydrogen atoms. If the hydrogen atoms on adjacent carbon atoms are missing, the two carbons (which are already bound by one bond) form a second bond, and these are called double bonds. A fatty acid lacking the maximum number of hydrogen atoms is called an unsaturated fatty acid. The most common fatty acid in the human body is palmitic acid (16:0, which designates sixteen carbon atoms and no double bonds). Oleic acid (18:1) is the next common fatty acid. The diet provides linoleic (18:2) and linolenic (18:3) acids, which are called "essential fatty acids," meaning fatty acids that are essential to life and health and cannot be synthesized by the human body. Linoleic acid is converted via arachidonic acid to a series of compounds with hormonal activity called prostaglandins. The prostaglandins are usually made within the tissue in which they act and are involved in diverse functions such as control of inflammation, uterine contraction during labor, and blood platelet aggregation. An important group of long-chain polyunsaturated acids (polyunsaturated fatty acids [PUFAs]) occur in the fats of cold-water fish such as salmon and cod. The two principal PUFAs are eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6). While these fatty acids do not necessarily affect blood cholesterol levels, their presence in the diet has been associated with a reduced risk of cardiovascular disease.They have been shown to be essential to development of normal vision and also to influence brain development in newborns (Innis, 1991).

Phospholipids are glycerol derivatives in which two of the hydroxyls are esterified to fatty acids and the third to phosphoric acid, which is, in turn, esterified to a base. In lecithin, the most abundant phospholipid, the base is choline. The fatty acid in the 2 position of a phospholipid is usually polyunsaturated. It is often arachidonic acid (20:4), a product of metabolism of essential fatty acid, and a direct precursor of prostaglandins.

Biochemistry

Blood is an aqueous medium that contains an appreciable amount of lipid. Normal blood serum or plasma appears as a pale yellow, clear liquid, because the fat has been emulsified to give water-soluble fat-protein aggregates. These aggregates are designated as lipoproteins and have a lipid core and a protein coat. Fat enters the lymph in the form of chylomicrons, which are large triglyceride-rich particles. In the course of circulation the triglyceride is deposited in or metabolized by cells and the particles become smaller in size. The lipoproteins can be separated physically on the basis of their hydrated density and are designated as very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Although estimations of the lipid composition of the various lipoproteins are available, their size and shape may vary.

The proteins surrounding the lipid core (apoproteins) have been characterized and their biological functions catalogued. Thus, apolipoprotein AI (ApoAI) and apolipoprotein AII (ApoAII) are present only in HDL and are required for metabolism of the lipid portion of HDL. ApoAI activates lecithin-cholesterol acyltransferase, which is active in the synthesis of cholesterol esters, and ApoII is required for breakdown of the triglycerides by lipoprotein lipase.

Apolipoprotein B (ApoB) occurs only in LDL and is required for secretion of the triglyceride-rich lipoproteins. The exclusivity of ApoA and ApoB to HDL and LDL, respectively, is often used for determination of LDL/HDL ratios. Apolipoprotein E (ApoE) is present in both VLDL and HDL. It occurs in several modifications (isoforms), which may determine level of success in treatment of hypercholesterolemia and which have been hypothesized to influence susceptibility to Alzheimer's disease. An LDL variant, Lp(a), appears to confer increased susceptibility to atherosclerosis, and its presence in serum is often used as an additional diagnostic indicator. The principal lipoproteins, LDL and HDL, are known popularly as the "bad" and the "good" cholesterol.

Elevated levels of LDL are a risk factor for heart disease, hence LDL is considered to be a "bad" lipoprotein. Elevated HDL levels lower the risk of heart disease, hence the designation '"good" cholesterol. LDL is rich in cholesterol and delivers cholesterol into cells, whereas HDL, which is about 50 percent protein, aids in cholesterol egress from cells.

Heart Disease

There is a roster of risk factors that are associated with an increased chance of succumbing to heart disease, but none of these factors is an unequivocal risk. Risk in places like Las Vegas is called "odds." There are a number of well-documented risk factors for development of coronary heart disease. Heredity and age are beyond control. The others are elevated blood pressure, elevated blood cholesterol, smoking, obesity, diabetes, physical inactivity, and stress. Each factor exerts its effects differently in each individual. These factors may also interact. It is now becoming accepted that the initial injury in atherosclerosis may be inflammation, which complicates the risk picture (Ross, 1993). There are suggestions that infection in some way prepares the arterial tissue for the subsequent metabolic events. At present we must monitor the various controllable risk factors, bearing in mind the possibility that a prior event may determine the extent to which the risk factors affect risk. In the United States, deaths from heart disease (cases per 100,000, adjusted for age) peaked in 1968 and have been falling since then. Between 1960 and 1998 mortality from all causes in men fell by 33.8 percent and coronary heart disease mortality by 51.0 percent. In women the reductions were 33.7 and 50.1 percent, respectively. Incidence of the disease may be rising as population increases and other modes of demise diminish or disappear. A century ago the major causes of death were related to infection, while a half-century ago the average age of victims of coronary disease was considerably below what it is today. This is a public health triumph due to improved diagnosis and treatment. The aim now should be to achieve productive and healthy aging.

Of the risk factors cited above none has received more attention than blood cholesterol. Dietary studies related to atherogenesis were conducted early in the twentieth century; they usually involved a combination of dietary alterations plus physical stress. The earliest purely nutritional study was carried out by Ignatowski in 1909. He observed aortic atherosclerosis when weanling rabbits were fed milk and egg yolk or when adult rabbits were fed meat. A few years later Anitschkow (1913) fed rabbits cholesterol and reported atherosclerotic lesions and fat deposition. Anitschkow's work established dietary cholesterol as the modality for establishment of atherosclerotic-like lesions, and this was carried over to human nutrition; consequently dietary cholesterol was presumed to be the principal contributor to cardiovascular disease. Relatively mild interest in cholesterol and atherosclerosis was evinced in the research and medical communities for the few decades after Anitschkow's publications. In the late 1940s and early 1950s interest in cholesterol intensified. The reasons for this renewed interest were an increase in death from coronary disease, as death from infectious causes waned and new research findings, especially Gofman's demonstration of the separation of different lipoprotein classes, which differed in their chemistry (Gofman et al., 1950). The cholesterol-rich lipoproteins were associated with greater susceptibility to heart disease. Subsequently the research area developed the concept of risk factors, of which elevated blood cholesterol was the first clearly defined one. At about the same time epidemiological studies, many conducted by Ancel Keys, began to show that populations whose diets were rich in cholesterol and fat demonstrated high death rates from heart disease.

At this point it might be important to distinguish between the effects of dietary cholesterol and dietary fat. While there is no argument that blood cholesterol is a risk factor for coronary disease, the connection with dietary cholesterol is not strong.The connection between dietary cholesterol and blood cholesterol is controversial. The data show that the amount of dietary cholesterol plays a lesser role in affecting blood cholesterol than does the type of dietary fat. Dietary cholesterol plus saturated fat is much more cholesterolemic than the same amount of cholesterol plus unsaturated fat (McNamara, 1987). Since dietary cholesterol is often accompanied by saturated fat, it is considered prudent to limit its intake. Gertler et al. (1950) reported a study in which they had segregated from a large cohort of coronary patients and controls four groups of ten men each, those who ate the most cholesterol and those who ate the least, and those with highest or lowest plasma cholesterol levels. In every subgroup the coronary patients exhibited significantly higher plasma cholesterol levels than did the controls—thus confirming the role of cholesterol as a risk factor. However, in no group did the investigators find any correlation between dietary cholesterol intake and blood cholesterol level. Thirty years later an attempt was made to correlate diet with coronary disease in three large populations under continuous study. The populations were in Framingham, Massachusetts; Puerto Rico; and Hawaii. Diets of men who had had a coronary event and those who had not differed significantly in total calories (lower in cases), complex carbohydrate (lower in cases), and alcohol intake (lower in cases). Intake of fat or cholesterol was the same in cases and controls (Gordon et al., 1981).

Type of dietary fat affects atherogenesis in rabbits and cholesterolemia in humans. Keys (1965) and Hegsted (1965) and their colleagues showed that fats rich in saturated fatty acids promoted cholesterolemia. They developed formulas to predict changes in blood cholesterol based on dietary saturated and/or unsaturated fatty acids. Since the publication of the original formulas many revised and refined versions have appeared. The new formulas provide coefficients for specific fatty acids, but none has proved to be more serviceable or useful than the originals. It should be pointed out that even the most saturated dietary fat, coconut oil, contains oleic (about 7 percent) and linoleic (about 2 percent) acids, and that one of the most unsaturated fats, safflower oil, contains about 7 percent palmitic acid and 2 percent stearic acid. In the Keys and Hegsted formulas stearic acid is viewed as "neutral" because it has no effect on blood cholesterol.

An issue that has been debated for several decades is the role of trans-fatty acids. In most naturally occurring unsaturated fatty acids the hydrogen atoms attached to the carbons that constitute the double bond are spatially on the same side of the molecule (cis); when they are on opposite sides, they are designated as "trans." There are many trans fats in nature but not many in our usual diet. However, trans double bonds may be formed during hydrogenation of fat used for margarines. The major source of trans fat in the diet is margarine and baked goods made with margarines or margarine stock. Concerns over diets high in trans fats were aired in the 1940s and 1950s. It was found then that in rabbits fed atherogenic diets trans fat elevated cholesterol levels but did not increase severity of atherosclerosis (McMillan et al., 1963). The question of trans fat effects is complicated because hydrogenation may provide fats with double bonds anywhere from carbon 4 to carbon 14 of the fatty acid. Recent research shows that trans fat lowers levels of HDL-cholesterol in humans. It has also been demonstrated that trans fats have little effect in diets containing high levels of polyunsaturated fat. Because of health concerns margarine manufacturers have begun to produce products containing little or no trans-unsaturated fat (Kritchevsky, 1999b).

Ingestion of cholesterol per se appears to have little effect on cholesterolemia. Numerous studies have shown that eggs, the richest source of cholesterol, have little effect on blood cholesterol (McNamara, 2000). However, most cholesterol in the diet is associated with animal fats, which are more saturated than plant fats. Hence the admonition to exercise prudence in ingestion of cholesterol.

The field of fat and cholesterol is still active and as new fats and new facts emerge dietary suggestions will be modified. At one time we were admonished to eat a virtually fat-free diet, but fat is a necessary nutrient. Very low-fat diets present their own problems, since diets too high in carbohydrate may affect insulin metabolism and can lead to triglyceridemia (Lichtenstein and Van Horn, 1998). In the 1950s high plasma triglyceride levels were considered to be an independent risk factor for coronary disease. For a long while triglyceride levels were virtually ignored, but they are beginning to reassume importance as new clinical and epidemiological data appear. Similarly, the appreciation of specific aspects of fatty acid effects has led to changes in recommendations regarding their intake. At one time the entire emphasis was on polyunsaturated fat, but it was shown that this type of fat lowered both LDL and HDL cholesterol whereas monounsaturated fat (olive oil, for instance) reduced only the "bad" lipoprotein (LDL), leading to a more acceptable LDL-cholesterol/HDL-cholesterol ratio (Mattson and Grundy, 1985). These observations have led to support of the "Mediterranean diet," which is rich in monounsaturated fat but also contains more vegetables and fruit than does the present American diet.

In general terms, current recommendations suggest a diet containing 30 to 35 percent calories from fat with no more than 7 to 10 percent being saturated fat and about 30 to 40 percent carbohydrate, with adequate levels of dietary fiber. Liberal intakes of vegetables and fruit (five to seven servings per day) are also recommended as we begin to find that various plant constituents (carotenoids, flavonoids, phytosterols) may contribute to cardiovascular health. The role of caloric intake is not always addressed directly, but obesity is looked upon as a risk, and daily physical activity is encouraged (Krauss et al., 1996, 2001).

Our view of coronary disease keeps changing with new research findings. Whereas it was originally thought to be simply fat deposition, we now view it as an inflammatory process that can be stimulated by oxidized cholesterol and specific growth factors (Ross, 1993). The initial inflammation may be caused by viral or bacterial infection. The size of the LDL particle may be important; thus small, dense LDL particles may indicate increased risk even in the face of normal lipid levels (Krauss and Burke, 1982). Lipoprotein (a), a slightly altered LDL, affects blood clotting and may be an independent risk factor (Loscalzo, 1990).

The question of established and emerging risk factors has been addressed. The well-established, major risk factors continue to be cigarette smoking, hypertension, elevated serum cholesterol, elevated LDL cholesterol, low-HDL cholesterol, diabetes, and aging. Additional factors that predispose to coronary disease are family history of premature coronary disease (genetics), obesity, physical inactivity, and psychosocial factors (stress, for instance). Other risk factors are also beginning to appear—some are general and the causative actions of some are not clear. Among these are elevated serum homocysteine levels, first suggested over thirty years ago and possibly connected with metabolism of folic acid and vitamins B₆ and B₁₂ (Malinow et al., 1999). C-reactive protein (CRP) is a general marker of inflammation produced in the liver in response to bacterial infection or physical trauma. The risk of coronary events is elevated in subjects with elevated levels of cholesterol and CRP (Ridker et al., 1999).Coronary heart disease is related to elevated serum lipids, diabetes, and obesity. All may be influenced by diet but the view of diet becomes more sophisticated and goes beyond dietary fat, although fat still plays a significant role. There is a plethora of risk factors of varying significance, and we still have no unequivocal indication of which subject's risk is affected by which particular factor.

Cancer

The role of fat in cancer has also been the subject of much research inquiry. In a classic study, Armstrong and Doll (1975) investigated the effects of diet on a number of cancers. Positive associations were found between total fat consumption and colorectal or breast tumors. Animal studies showed that a high-fat diet was more co-carcinogenic than a low-fat diet and that unsaturated fat was more co-carcinogenic than saturated fat. The latter result were due to the fact that linoleic acid is a growth factor for tumors (Carroll and Khor, 1971).

The data concerning fat and cancer risk are inconsistent. High intake of fat is a marker for a high-calorie diet and it is possible that it is the caloric contribution of fat rather than fat itself that is the culprit. Hoffman (1913) suggested that "erroneous diet" was a factor in the etiology of cancer. Excess body weight has been correlated with cancer mortality (Garfinkel, 1985). Animal studies dating to 1909 show that caloric restriction leads to reduced tumor growth. Lavik and Baumann (1943) showed that the incidence of methylcholanthrene-induced skin tumors in mice fed a diet high in fat but low in calories was 52 percent lower than that seen in mice fed a diet high in calories but low in fat. It has also been shown that incidence of dimethylbenz(a)anthracene induced mammary tumors in rats fed 5 percent fat ad libitum is lower than in rats fed a diet containing 20 percent fat but whose energy intake is restricted by 20 percent (Klurfeld et al., 1989).

Epidemiological studies have shown a positive correlation between energy intake and breast or colon cancer risk. The factors underlying the cancer-inhibiting effects of energy restriction are under study. Energy restriction leads to reduction in circulating insulin, and insulin is a growth factor for tumors. Energy restriction also reduced oncogene expression and leads to enhanced DNA repair (Kritchevsky, 1999a).

Diet

When all of the above has been said, the question each of us must answer remains, "What should I eat?" Dietary suggestions have ranged from the four food groups (meat, carbohydrates, dairy, and fruits and vegetables) to the United States Department of Agriculture (USDA) pyramid. The USDA pyramid is an attempt to illustrate which foods should be eaten in which amounts. The broad base of the pyramid represents large quantitites of grains and starches, and the narrow peak represents small quantities of fats and oils. Other dietary components are displayed between the peak and the base and their position in the pyramid represents the relative suggested levels of intake. The idea is to incorporate the best dietary information of the day into a healthful eating pattern. The "Dietary Guidelines for Americans" are written by select committees appointed by the United States Departments of Agriculture and Health and Human Services, and the publication is disseminated under their joint sponsorship. The guideline recommendations have changed relatively little in the past few decades, but the changes that appear reflect current findings and opinion. We are told to maintain ideal weight, although nobody is certain what that means. Originally we were advised to eat a diet that would provide protection against the ravages of infection, but now we are intent on protection against degenerative diseases, heart disease, and cancer, for which we have developed a catalog of risk factors but have no unequivocal diagnoses. Another general factor that we did not have to deal with in the past is the rise in obesity.

Vegetables and fruits provide chemicals that, in the laboratory, protect against cancer and heart disease and provide little or no fat. Grains are part of a healthful diet because they provide complex carbohydrate and fiber. Meat provides high-grade protein, necessary trace minerals (zinc, manganese, iron) and vitamin B₁₂, but fear of its fat content is reflected in advice to limit its consumption. Dietary fats are limited because of their caloric content, but they contain the essential fatty acids. Advice about dietary components is presented with the implied view that they are metabolized in a similar manner despite their quantity or presence of other nutrients in the diet. There is virtually no information concerning interaction of individual nutrients.

Fat is feared because of its caloric density and its connection with the risk of heart disease or cancer. The food industry is capable of producing foods that address current concerns. We have available a host of fat-free snacks, but their caloric content is rarely different from the fatrich food they are replacing. Thus, influence on a risk may be diminished but there is no effect on body weight. Very low-fat diets are criticized as unhealthy. Diets high in carbohydrate may affect insulin metabolism, and there are some investigators who believe that insulin resistance may underlie both cancer and coronary disease.

General dietary advice—enough essential nutrients to maintain health—is constant but the specifics are distributed on an ad hoc basis depending on current knowledge. A case in point is the avocado. Thirty or so years ago this fruit was not recommended because of its fat content. Today we know the fat is monounsaturated ("good") and the avocado also contains generous quantities of various carotenoids. The avocado is now recommended by nutritionists everywhere. Fat content?—well, just don't eat too much of it. Carotenoids are a family of chemicals that occur in highly colored fruits and vegetables. Some may be precursors of vitamin A. The most common carotenoid is lycopene, which occurs in tomatoes.

To return to the specifics—namely, what we should eat—we still mean a "well-rounded" diet, to be taken in quantities that do not influence body weight. Suggestions to exercise regularly are also becoming part of dietary advice, again for purposes of weight control. Sugary snacks and sugar-rich beverages should be kept to a minimum. The ideal diet, in addition to its content, requires input from the consumer—namely, a measure of discipline.

Healthful diets go beyond "one size fits all." Growing children have different requirements than adults. The elderly may require different levels of various nutrients, and the active elderly have different needs than do the infirm elderly.

So we come down to the general advice of a little of everything but not too much of anything. The advice has to consider age, activity, and health status. Eating should be a pleasurable, social activity and not feared as the specific arbiter of life and death. The best advice for the average healthy person is variety, balance, and moderation. The watchword should be: Moderation, not Martyrdom.

See also Assessment of Nutritional Status; Dietary Assessment; Dietary Guidelines; Disease: Metabolic Diseases; Fats; Intake; Mediterranean Diet; Nutrition; Vitamins.

David Kritchevsky