Dietary lipids: more than just a source of calories

The title of our editorial last year ‘New metabolic pathways and roles for lipids and lipid emulsions’ [1] would be an appropriate title again this year, because the past 12 months have seen continued intense interest in the metabolism of lipids both intra- and extracellularly, in the physiological effects of different classes of fatty acids, and in the ways that these effects are exerted. The findings of these studies emphasize, once again, that lipids are more than sources of energy and of building blocks for cell membranes, but may, in some circumstances, be considered as pharmacological agents provided through nutrition. This appears to be particularly true of the long chain n-3 polyunsaturated fatty acids (PUFAs) found in oily fish; these fatty acids are eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3). It is now clear that n-3 PUFAs exert a number of effects that will be beneficial in cardiovascular disease and also in inflammatory diseases and some cancers. Recent developments concerning some of these effects are reviewed in the current issue by Klaus Wahle and Dino Rotondo (pp. 109-115), by Stefan Endres et al. (pp. 121-126) and by Philippe Bougnoux (pp. 117-120). It now appears that these and other fatty acids can regulate the expression of genes involved in lipid metabolism (see the review by Worgall and Deckelbaum, pp. 127-133) and also in inflammation (see Wahle and Rotondo, pp. 109-115). The realization that long-chain n-3 PUFAs might elicit effects that are beneficial to human health has rekindled interest in the metabolism of PUFAs (both n-6 and n-3), and the article by Howard Sprecher (pp. 135-138) provides an update on these metabolic pathways; this update describes some of the intricate studies that have been performed to reveal these pathways in detail. Another area of activity has been the development and use of preparations containing n-3 PUFAs and other types of biologically active fatty acids for incorporation into parenteral or enteral nutrition regimens. Recent developments in these areas are reviewed in this issue by Isabelle Dupont and Yvon Carpentier (pp. 139-145) and Trevor Redgrave (pp. 147-152). A common theme in recent studies is the regulation of the production of mediators and of cellular interactions by n-3 PUFAs, often by effects at the level of gene expression that might be mediated by the redox status of the cell. The interaction of dietary PUFAs with dietary antioxidants (especially α-tocopherol) is thus an important one in terms of determining the ultimate physiological outcome. A number of studies have reported that either eicosapentaenoic acid or docosahexaenoic acid or both decrease the expression of certain adhesion molecules on the surface of endothelial cells [2,3], monocytes [4] and lymphocytes [5], although not all studies agree on the precise effects of the different n-3 PUFAs or of arachidonic acid. The n-3 PUFAs appear to act at the level of adhesion molecule gene expression, because messenger RNA levels for the adhesion molecules are decreased after the incubation of cells with these fatty acids. Feeding rats a diet rich in fish oil or supplementing the diet of healthy humans with n-3 PUFAs decrease adhesion molecule expression on the surfaces of lymphocytes [6] and monocytes [7], respectively. This was accompanied by a functional change, i.e. decreased adhesion of lymphocytes from fish oil-fed rats to ligand-bearing cells (macrophage or endothelial cell monolayers) [6]. Wahle and Rotondo (pp. 109-115) discuss these findings and suggest that the effects of different PUFAs may be mediated by changes in the activities of transcription factors that are sensitive to the intracellular redox status. Whatever the mechanism of action, these observations suggest that fish oil will influence leukocyte movement between body compartments and might decrease movement into sites of inflammatory activity and into atherosclerotic plaques. As such, this would be a novel anti-inflammatory and anti-atherosclerotic mode of action for fish oil. Wahle and Rotondo (pp. 109-115) also discuss the influence of n-3 PUFAs on cytokine production, another area of conflicting observations (see [8] for a review); again it appears that n-3 PUFAs might regulate pro-inflammatory cytokine (and cytokine receptor [9]) gene expression, and this might be another anti-inflammatory and anti-atherosclerotic action of fish oil. Such observations indicate that fish oil supplementation might be a useful therapeutic tool in diseases involving the inappropriate production of pro-inflammatory mediators. In this issue their effectiveness in inflammatory bowel disease is reviewed by Endres et al. (pp. 117-120). n-3 PUFAs also exert effects on the growth of various tumour cell lines in vitro, causing their death by either necrosis or apoptosis, depending upon the cell type [10] (see Bougnoux, pp. 121-126). At least some of these effects appear to be exerted through processes involving changes in the redox status of the tumour cells. Such effects appear to make some tumours more sensitive to radiation and chemotherapy. Over the past 12 months or so a number of animal studies have reported the effects of n-3 PUFAs and other dietary fatty acids on tumour growth in a variety of models (see Bougnoux, pp. 121-126). These animal studies tend to suggest that n-3 PUFAs may have protective effects towards colorectal, hepatic and breast tumour growth, but the interaction between PUFAs and the levels of dietary antioxidants remains to be established. Human studies [11] do, however, continue to support a protective role for n-3 PUFAs in colorectal cancer. Eicosapentaenoic acid has also been effective when used in weight losing pancreatic cancer patients [12]. The effect of different fatty acids and other dietary lipids, such as cholesterol, on blood lipid concentrations and in turn upon the risk of cardiovascular disease has been known for some time. It has, however, only recently been appreciated that the effects of different dietary lipids upon blood triacylglycerol and cholesterol concentrations are most likely exerted largely at the level of expression of genes involved in lipid metabolism, especially in the liver (reviewed in [13]) and adipose tissue (reviewed in [14]). Worgall and Deckelbaum (pp. 127-133) update this field, highlighting recent findings with respect to the molecular mechanisms by which different fatty acids interact with the regulatory sequences that control a number of genes involved in hepatic and adipose tissue lipid metabolism. Although there has been much recent excitement about the interaction of PUFAs and their derivatives with the class of transcription factors known as peroxisome proliferator-activated receptors (PPARs) [15] (such interactions might also play a role in the regulation of inflammation by PUFAs [16]), it is now becoming apparent that there are other non-peroxisome proliferator-activated receptor-mediated mechanisms by which fatty acids can influence the metabolism of lipids (see Worgall and Deckelbaum, pp. 127-133) and perhaps other cellular functions. Lipids were originally included as components of enteral and parenteral nutrition regimens as a source of calories. More recently, however, there has been a move to include specific types of lipids with desirable functions beyond their roles as fuels. These lipids include medium-chain triacylglycerols (MCTs), n-3 PUFAs and lipid soluble vitamins. Dupont and Carpentier (pp. 139-145) review a number of recent studies investigating the metabolism of various lipid emulsions and their clinical applications. Emulsions containing either MCTs or n-3 PUFAs have been used in a number of clinical settings with favourable results; they have often been used in patients at risk of inflammatory complications, and many of the observations made (e.g. reduced leukotriene B4 production with an enhanced ratio of leukotriene B5 to leukotriene B4 and a smaller post-surgery rise in pro-inflammatory cytokine production [17]) agree with those made with isolated cell cultures or animal feeding experiments. If they are to be used more routinely in clinical practice n-3 PUFA-rich emulsions will need to be protected against oxidative damage both before and after infusion. The inclusion of α-tocopherol appears to be an important protective step (see Dupont and Carpentier, pp. 139-145). Clearly it will be important to achieve the optimal balance between PUFAs and antioxidants. Although MCTs and n-3 PUFAs appear to offer alternative, functional components partly to replace the traditional soybean oil-based, n-6 PUFA-rich lipid emulsions, a new olive oil-based emulsion is being promoted largely on the basis of its lack of biological effects [18]. Redgrave (pp. 147-152) highlights the wide potential for enteral nutrition and again describes the use of n-3 PUFA-enriched formulations. A number of studies have demonstrated improved outcomes in post-surgical patients administered such formulations (see Redgrave, pp. 147-152), but these often contain a mixture of pharmacologically active nutrients (e.g. arginine, n-3 PUFAs, nucleotides, antioxidants), and it is difficult to attribute their effectiveness to a single component. Redgrave (pp. 147-152) also discusses the potential use of enteral nutrition for delivering various lipid-soluble agents. In summary, and as we highlighted last year [1], certain fatty acids are undoubtedly biologically active. The key task in taking full advantage of their effects in public health and clinical settings is to gain a better understanding of their mechanisms of action (e.g. at the level of gene expression) and their interactions with other active nutrients (e.g. α-tocopherol). The reviews in this issue indicate that we are on our way to a better understanding of these issues but that much remains to be learned.