Fish oil prevents essential fatty acid deficiency and enhances growth: clinical and biochemical implications
Introduction
Fatty acids are major cellular constituents that form integral parts of the cell membrane and impact the membrane's fluidity and function. Within the plasma lipoprotein particles, fatty acids serve as the major constituents of phospholipids, triglycerides, and cholesterol esters. In mammalian cells, there are 3 important types of fatty acids: omega-3, omega-6, and omega-9. Both the omega-3 and omega-6 fatty acids are considered essential fatty acids (EFAs) in mammals because they cannot insert double bonds at position-3 and -6 to produce α-linolenic acid (ALA) and linoleic acid (LA), respectively, and thus must be obtained from the diet. Cell membrane composition is determined by dietary intake of either of these EFAs. More importantly, LA and ALA are essential nutrients in that all downstream polyunsaturated fatty acids can be synthesized from them. Among these downstream products are several highly physiologically relevant fatty acids: arachidonic acid (AA, derived from LA), docosahexaenoic acid (DHA, derived from ALA), and eicosapentaenoic acid (EPA, derived from ALA) [1]. These are considered to be critical metabolites because they are important eicosanoid and prostanoid precursors. Currently, the suggested ratio of omega-6 to omega-3 fatty acids is variable and without consensus. Previous recommendations suggest a balance of 10:1, although emerging data indicate that a ratio as low as 2:1 may be optimal [2], [3].
Essential fatty acid deficiency (EFAD) results from low dietary intake, severe malabsorption, and/or increased physical requirements such as growth [4]. In 1971, Holman [5] described the symptoms of EFAD in rats and other mammalian species, including primarily impaired growth and dermatitis and secondarily steatosis, renal toxicity, pulmonary abnormalities, and increased metabolic rate. In EFAD, tissue levels of both omega-3 and omega-6 fatty acids are diminished. The major biochemical changes of EFAD are decreased AA and increased Mead acid, the latter being a downstream product of oleic acid, an omega-9 fatty acid. Desaturase enzymes display differential activity in the order of preference omega-3 > omega-6 > omega-9. Normally, LA would be converted to AA, a tetraene; however, in times of deficiency, de novo lipogenesis occurs, resulting in the conversion of oleic acid by elongation and desaturation to Mead acid, a triene. As a result, conversion of oleic acid to Mead acid only occurs when there are low dietary levels of both ALA and LA. This metabolic switch is seen as a compensatory mechanism to maintain the number of double bonds in cell membrane fatty acids. Therefore, elevated Mead acid in conjunction with a lowered AA has been associated with EFAD [6], [7]. Until recently, plasma ratios greater than 0.2 were considered abnormal, whereas levels greater than 0.4 were considered diagnostic for EFAD [8]. Currently, triene-tetraene ratios no greater than 0.2 have been suggested as the average ratio in Western populations, as diets rich in omega-6 fatty acids resulted in ratios that were found to be only 0.1 ± 0.08 [9]. The triene-tetraene ratio does not reflect omega-3 fatty acid status. Standard minimum intake to meet LA requirements is set to 1% of total caloric intake in animal studies. In certain conditions, AA, EPA, and DHA may be considered conditionally EFAs, as their production may be inadequate. Young animals deprived of dietary intake of LA and ALA rapidly display adverse effects such as diminished growth, liver and kidney damage, dermatitis, and eventually death. Human studies have shown that estimated optimal daily requirements of LA are 1% to 3% of total caloric intake, increasing proportionally with growth [5], [10]. The minimum ALA acid concentrations in the diet have been reported to be 0.2% to 1% of total caloric intake in adults and 0.5% in infants and young children [11], [12], [13], [14]. Despite their conditionally essential status, no similar dietary recommendations have been made for AA, EPA, or DHA.
Renewed interest in the clinical use of fish oil has appeared because of their high omega-3 fatty acid content [15]. Although the body is able to synthesize AA from LA, and EPA and DHA from ALA, unlike other oils, fish oil appears to be a more efficient source of these fatty acids because it does not rely on conversion from their 18 carbon precursors. However, concerns have emerged that diets exclusive in this fat source may predispose patients to EFAD and subsequent growth failure because fish oil does not fulfill the aforementioned 1% minimum requirement of LA. Recent reports involving parenterally fed pediatric patients receiving diets using fish oil as their only fat source suggest otherwise [16], [17], [18]. In each instance, patients with preexisting EFAD had their condition reversed or prevented with fish oil; and growth was maintained.
The objectives of this study were to establish biochemical standards and EFA profiles for diets with differing lipid compositions. We hypothesized that menhaden fish oil contains sufficient amounts of EPA, DHA, and AA to prevent biochemical and clinical EFAD.
Section snippets
Nutritional model
Animal protocols complied with the National Institutes of Health Animal Research Advisory Committee guidelines and were approved by the Children's Hospital Boston Animal Care and Use Committee.
Forty 6- to 8-week–old C57/Bl6 mice (Jackson Laboratories, Bar Harbor, ME) were housed in a barrier room. Before the initiation of the study, mice were fed a baseline chow (Prolab Isopro, RMH 3000 #25; Prolabs Purina, Richmond, IN). After 3 days of acclimatization, they were divided into 2 groups: ad
Animals
Throughout the 9-week experiment, all animals in both the pair-fed and ad libitum groups were clinically well. None of the animals showed any physiologic signs of EFAD, such as dermatitis, alopecia, or infections. Although the development of dermatitis is a valid and sensitive physiologic measure of EFAD, animals in this study were not allowed to develop the extent of EFAD necessary for its development because of institutional animal research regulatory constraints. Growth retardation is
Discussion
Parenteral nutrition (PN) has been used for many years to provide calories and essential nutrients to patients who are unable to obtain them through the enteral route. Among the first major obstacles associated with the use of PN was the induction of EFAD in recipients of this therapy [28], [29], [30]. In response, a soybean emulsion was introduced to provide EFAs and thus prevent deficiency [31]. Recent studies have shown that lipid metabolism is altered by its route of administration;
Acknowledgment
Mr Strijbosch was funded by Trustfonds Erasmus Universiteit Rotterdam (Rotterdam, the Netherlands), Dr Saal van Zwanenberg Stichting (Oss, the Netherlands), VSB fonds (Den Haag, the Netherlands), and Michaël van Vloten fonds (Venray, the Netherlands). Dr Puder is funded by National Institutes of Health grant DK069621-03 and the Children's Hospital Surgical Foundation (Boston, MA).
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