Nutritional regulation of long-chain fatty acid profiles and metabolism
Phospholipids of all cellular and subcellular mem-branes contain a diverse range of long-chain fatty acids, the profile of which is subject to both dietary influence and endogenous control. A few organs, notably the brain, maintain extraordinarily strict control of their membrane composition. However, the fatty acid profile of most organs is usually respon-sive to the influence of changes in dietary fatty acid composition and other nutritional variables, yet maintains the vital “gatekeeper” functions of all mem-branes. Hence, when changes in dietary fat alter membrane fatty acid profiles, appropriate membrane fluidity can be maintained by the addition or removal of other lipids such as cholesterol. Insufficient energy intake and the presence of disease have important consequences for fatty acid synthesis, desaturation, and chain elongation and, consequently, tissue fatty acid profiles.
Inadequate energy intake increases macronutrient oxidation, including fatty acids. Short-term fasting followed by refeeding a carbohydrate-rich meal is the classic way to stimulate fatty acid synthesis. Insulin is implicated in this process. When repeated, fasting/ refeeding or weight cycling induces a gradual increase in the proportion of saturated and monounsaturated compared with PUFAs in tissues, especially body fat. This shift occurs because of the increase in fatty acid synthesis, easier oxidation of polyunsaturates, and the inhibition of desaturation and chain elongation by fasting. The implications of such an alteration in tissue fatty acid profiles have not yet been extensively studied, but probably involve changes in insulin sensitivity and other hormone effects. Protein deficiency also inhibits desaturation and chain elongation of PUFAs.
Copper supplementation increases 9 desaturase activity in animals, resulting in higher oleate levels. This effect was first observed when copper was used to reduce gastrointestinal infection in pigs, but also led to softer back fat. Opposite to the effects of copper supplementation, copper deficiency inhibits synthesis of both oleate and docosahexaenoate.
There are four key features of the nutritional regula-tion of the profiles and metabolism of PUFAs. These attributes govern the effects of deficiency or excess of one or more of these families of fatty acids almost as much as their level in the diet. These key features are:
1 specificity within families
2 competition between families
3 substrate and end-product inhibition
4 cofactor nutrients.
An n-6 PUFA cannot be converted to an n-3 or n-9 PUFA. Thus, deficiency of one family of polyunsatu-rates cannot be corrected by excess of those in a dif-ferent family and, indeed, is exacerbated by excess intake of the other families.
The three families of PUFAs appear to use a common series of desaturases and chain elongases. The prefer-ence of these enzymes is for the more unsaturated fatty acids so, everything else being equal, more α-linolenate will be desaturated than linoleate or oleate. However, in practice, more linoleate is consumed than α-linolenate and, as a result, more arachidonate is produced endogenously than eicosapentaenoate. Furthermore, this competition for desaturation and chain elongation between linoleate and α-linolenate can lead to exacerbation of symptoms of deficiency of one or other fatty acid family. Thus, as has been demonstrated both clinically and experimentally, excess linoleate intake using sunflower oil is a common way to accelerate deficiency of n-3 PUFA.
Excess linoleate or α-linolenate intake appears to inhibit production of the respective long-chain prod-ucts in the same fatty acid family, i.e., high α-lino-lenate intake inhibits synthesis of docosahexaenoate.
Likewise, the main end-products of desaturation and chain elongation tend to inhibit further metabolism through this pathway, so arachidonate inhibits its own synthesis. Similarly, dietary deficiency of linole-ate increases activity of the 6 and 5 desaturases, presumably to restore depleted levels of long-chain n-6 polyunsaturates such as arachidonate.
The cofactor requirements of the desaturation chain-elongation enzymes are not yet well understood, but a few relationships are known. The desaturases are metalloenzymes containing iron, and iron deficiency therefore inhibits desaturase activity. Magnesium is needed for microsomal desaturase activity in vitro. Zinc deficiency inhibits 6 and 5 desaturation, appar-ently by interrupting the flow of electrons from NADH. This effect is severe enough that inherited forms of zinc deficiency such as acrodermatitis enteropathica cause a precipitous decline in plasma arachidonate, greater than usually observed with dietary deficiency of n-6 polyunsaturates.