Fats in the new millennium: more complexity but a better understanding?

Abstract

The impact of the type of fat in the diet on human disease has been increasingly recognized, and it is now established that certain fatty acids have biochemical and physiological properties that are associated with either detriments or benefits to human health. This has been the theme of many of the articles published in this section in previous years, and is a theme that is continued in the current issue. Some years ago it was proposed that an elevated postprandial plasma triacylglycerol response is pro-atherogenic [1], and the consumption of a high fat meal was demonstrated to cause such an elevation. In their article in this issue Griffin and Fielding (pp. 93-98) elegantly review the postprandial lipemic response and factors that affect this, focusing on more recent developments. A variety of dietary, lifestyle, hormonal and pharmacological factors influence the postprandial lipemic response. Among the more potent attenuators of postprandial lipemia are the long-chain n-3 polyunsaturated fatty acids (PUFA) found in fish oil. Recent studies, reviewed by Griffin and Fielding, extend this observation. In one study [2] adding fish oil to simvastatin in hyperlipidemic patients resulted in a lowering of the postprandial triacylglycerol response compared with the control group (simvastatin patients given corn oil), suggesting that fish oil is likely to be beneficial even in patients undergoing pharmacological treatment for hyperlipidemia. Other studies highlighted an emerging concept that we believe has widespread implications for the entire field of lipid metabolism, nutrition and therapy. The studies [3-5] found that the sensitivity to the effects of fish oil is related to the apolipoprotein E genotype of an individual. This observation provides clues as to why only some individuals are susceptible to the detrimental effects of diet whereas others are not, and why some individuals benefit from the effects of dietary change whereas others do not. In terms of public health, it is important to recognize that there may be responders and non-responders to any dietary change, and it is important to find out how to identify these individuals. Metabolic syndrome or syndrome X is the name ascribed to the combination of symptoms that increase the risk of coronary heart disease: central obesity, hyperlipidemia, insulin resistance and hypertension. In this issue, Distler and colleagues (pp. 99-103) describe the emergence of this syndrome among HIV patients treated with protease inhibitors, a phenomenon first described approximately 3 years ago [6,7]. The mechanisms that might underlie the development of metabolic abnormalities are described by Distler and colleagues. Some debate has centred on whether the metabolic abnormalities are caused by protease inhibitors or whether they result from the presence of HIV itself. However, a recent study in healthy subjects [8] showed that the inhibitors induce some abnormalities in the absence of HIV infection. The rapid emergence of this syndrome in this group of patients highlights the importance of increasing the understanding of lipid metabolism at the whole body level and of the factors that impact on it. Unusual fatty acid compositions of plasma or cells have been reported in a variety of diseases, including atopic diseases [9], cystic fibrosis [10], and rheumatoid arthritis [11]. Most often the abnormalities relate to the proportions of long-chain n-6 and n-3 PUFA. It has frequently been observed that the proportions of arachidonic acid (ARA 20 : 4n-6) and long-chain n-3 PUFA, such as eicosapentaenoic acid (20 : 5n-3), are lower than in control individuals [9-11], and significant interest has been shown in manipulating the compositions of target cells and tissues to induce clinical benefit. To maximize clinical benefit, the basis and meaning of the altered fatty acid compositions needs to be understood. The abnormalities in fatty acid composition could result from altered dietary habits, from the decreased synthesis of long-chain PUFA, from the increased utilization of long-chain PUFA, or from a combination of these. Although the alterations in fatty acid composition may result from the presence of disease, it is often assumed that they are in some way a cause of disease. If a low proportion of ARA is the cause of disease, it would seem sensible to normalize the ARA content of target cells and tissues. On the other hand, if a low proportion of ARA arises as a result of disease (e.g. through increased ARA mobilization to form eicosanoids that are involved in the disease process), then providing more ARA may be harmful. Aiming to restore the fatty acid composition of target body compartments to ‘normal’ may thus be inappropriate. In this issue, Christophe and Robberecht (pp. 111-113) describe recent work in cystic fibrosis, and suggest that the abnormalities in the proportions of n-6 PUFA that occur in this disease are a result of increased ARA turnover. They thus argue in favour of specifically enriching target cells and tissues in patients with cystic fibrosis with fatty acids, which will antagonize ARA, i.e. γ-linolenic acid (GLA; 18 : 3n-6) and the long-chain n-3 PUFA found in fish oil. In this issue, Calder and Zurier (pp. 115-121) review the role of cytokines and ARA-derived eicosanoids in rheumatoid arthritis and present evidence from cell culture, animal feeding and dietary supplementation studies to support the use of GLA and long-chain n-3 PUFA as anti-inflammatory agents. They also review the trials using these fatty acids in rheumatoid arthritis. Placebo-controlled, double-blind trials of fish oil in arthritis indicate of a range of clinical benefits [12]. Both Christophe and Robberecht and Calder and Zurier suggest that there may be added benefit from the combination of GLA with fish oil, because these might act to produce a more balanced profile of eicosanoids. Dose-response studies with GLA and fish oil alone and in combination in various patient groups have not been performed, and are necessary in order to optimize the benefit this approach can bring. In their article in this issue, Watkins and colleagues (pp. 105-110) review recent findings in bone remodelling, highlighting recent molecular work. In addition to those factors well-recognized to control bone turnover (parathyroid hormone, 1,25-dihydroxy-vitamin D3, pro-inflammatory cytokines and prostaglandin E2), it has recently become apparent that both leptin and statins play a role in the regulation of bone mass [13,14]. These observations serve to highlight the complexities that exist at the whole body level with respect to the interactions between the quantity and quality of dietary fat, blood lipid levels, hormones, cytokines, and pharmacological agents, and physiological systems. Given that ARA-derived prostaglandin E2 has several effects to enhance bone resorption, Watkins and colleagues suggest a role for fish oil-derived n-3 PUFA in promoting bone health. However, as in other areas, GLA may also be of benefit in this respect, and the combination of GLA and fish oil is untested. Although PUFA are important components of all cell membranes, their proportions vary according to cell type. The proportions of ARA and docosahexaenoic acid (DHA; 22 : 6n-3) are particularly high in the eye and the brain, and these fatty acids play an important role in the structure of, and signalling mechanisms within, these tissues. An adequate supply of these fatty acids is required to support optimal growth and development of the human brain and visual system. Because the capacity of the fetus and the newborn infant to synthesize long-chain PUFA is very poor, an exogenous supply of these fatty acids is particularly important during fetal life and in early infancy. During pregnancy the fetus is supplied with ARA and DHA from the maternal circulation, whereas after birth the newborn receives fatty acids from its mother in milk. Therefore, pregnant and lactating women need sufficient supplies of these fatty acids. The nature of the supply of these fatty acids to pre-term infants and to term infants who are not breast fed is an important consideration. In this issue, Forsyth and Carlson (pp. 123-126) review the role of these fatty acids in the mental and visual development of infants. Significant evidence exists that pre-term infants require ARA and DHA for adequate growth and development. Recent studies [15,16] also suggest that the provision of ARA and DHA to term infants who are not breast fed improves mental development. One fatty acid not mentioned in any of the articles in this issue is conjugated linoleic acid (CLA). CLA is a mix of isomers of linoleic acid formed by biohydrogenation processes in the rumen, and so the main sources in the human diet are cow's milk, dairy products and the meat of ruminants. Studies in laboratory rodents showed that CLA has anti-cancer, anti-obesity and anti-atherosclerotic properties [17]. Other recent animal experiments have indicated that CLA enhances immune function [18] and is anti-inflammatory [19]. However, these animal studies have included large amounts of CLA in the diet and most often have used a mixture of CLA isomers. Nevertheless, CLA potentially offers a number of health benefits in humans. It is ironic that animal products that have been much maligned for many years because of their high content of saturated fatty acids should be the major source of such a potentially beneficial fatty acid as CLA. The year 2000 saw the publication of the first studies reporting the effects of increased CLA consumption by healthy humans [20-23]. Providing healthy volunteers with a mix of CLA isomers (a total of 3 g CLA per day) for several weeks did not affect body weight, body composition, fat mass, fat oxidation, or energy expenditure [20], plasma concentrations of glucose, insulin and lactate or ratings of appetite [21], or immune function [22], although there was a transient fall in the plasma leptin concentration [21]. CLA (4.2 g/day) resulted in increased lipid peroxidation in healthy volunteers [23]. Such studies suggested that the enthusiasm for human health benefits from CLA may be premature. However, the studies used a mixture of several CLA isomers. It is likely that different CLA isomers will have different biological potencies, and it will be important to identify the active isomers and to determine their dose-response effects in humans. The articles in this issue highlight the importance of an appropriate supply of various PUFA in human development, and in the prevention and treatment of human disease. We foresee significant advances in this field in the early years of the new millennium. The advances in molecular and cell biology and the completion of the Human Genome Project provide new opportunities to understand the mechanisms of action of dietary fatty acids, other lipids and lipoproteins, and to elucidate more fully how and why different dietary fatty acids and lipids act to increase or decrease the risk of various diseases. Importantly, the use of these modern technologies will provide clues as to why only some individuals are susceptible to the detrimental effects of diet whereas others are not, and why some individuals benefit from the effects of dietary change whereas others do not. Understanding the sensitivity to dietary fatty acids at individual and population levels will be the key to increasing the likelihood of the success of schemes to implement dietary change. Ultimately preventative dietary advice will be provided to specific groups or on an individual basis, with a greater likelihood of success (if the advice is taken!). This will also be particularly important in the clinic, where specific lipid-based treatments will be targeted to those who are more likely to benefit from them. Such tailoring of preventative advice and treatment will obviously demand a range of foods and clinical products, and this will be a challenge to those involved in the development of such products.