Fatty acids deficiency states

What are the implications of these studies of n-3 fatty acid deficiency and subsequent repletion in rhesus monkeys to human beings 1 i rst. these data strongly suggest that any n-3 fatty acid-deficient state will be corrected by fish oil containing EPA and DHA or in other studies, a diet containing n-3 fatty acids from soy oil (18 3n-3 linolenic acid). The brain phospholipids will readily assemble the correct amounts of DHA in the sn-2 position of the phospholipid molecular species, furthermore, other fatty acids of the n-6 series, which occupy that position in the deficient state, will ultimately be removed and replaced by DHA. It is not certain yet if functional abnormalities would likewise be corrected because the appropriate function may need to take place at a certain stage of development or it may not occur at all or to a lesser degree when there has been biochemical correction. 

Diabetic animals develop signs of essential fatty acid deficiency earlier than normal ones on a diet deficient in essential fatty acids (Peifer and Holman, 1955). In the diabetic a reverse relation is present between the essential fatty acid content of the blood and the glucose level. Furthermore, it is well known that diabetics develop atherosclerosis easily, while diabetic women are known to suffer frequently from toxemia of pregnancy also. The prevalence of both diseases in diabetics might be related to the endocrine disorder itself but could equally well be due to the dietary measures. Especially the low carbohydrate-high fat diet, formerly so commonly described, must be considered as harmful in this respect. Even the resistance to radiation sickness is less in essential fatty acid deficiency states (Decker et al., 1950 Cheng et al., 1954, 1955, 1956 Deuel et al., 1953). 

The measurements of the total amount of various essential fatty acids as co-3 fatty acids in plasma, serum, or erythrocyte membrane phospholipids have been indicated as useful markers of essential polyunsaturated fatty adds. Essential fatty acid deficiency is a clinical condition that derives from inadequate status of co-3 and co-6 fatty acids however, the symptoms are nonspecific and may not present prior to marginal essential fatty acid status. Widely used biomarkers for bicx hemi( essai-tial fatty acid deficiency are mead acid and the triene/tetraene ratio. Howcvct, the total plasma triene/tetraene ratio has been considered the gold standard for essential fatty acid deficiency. Mead acid, or 5,8,11-eicosatrienoic acid (5,8,11-20 3 co-9) is synthesized from endogenous oleic acid and is increased when there is insufficient concentrations of linoleic and a-linolenic acid to meet the needs of polyunsaturated fatty acids. Under normal conditions only trace amounts of mead acid are found in plasma. EPA and DHA inhibit mead acid synthesis. Mead acid measurement is an indicator of essential fatty acid deficiency state, while essential fatty add depletion is associated with a decrease in plasma hnoleate and arachidonate percentages. Assessment of long-term essential fatty acid intake is measured in adipose tissue, and it is considered the best indicator because of its slow tumover. - Cutoff values for the assessment of essential fatty adds and to-3 fatty acid status in erythrocytes have been reported. Proposed cutoff values for children older than 0.2 years are 0.46 mol% 20 3 co-9 (mead acid) for early suspicion of essential fatty acid defidency, 0.068 mol/mol docosapentaenoic/arachidonic acid... 

In our previous reports, we have shown that infant rhesus monkeys born from mothers fed an n-3 fatty acid-deficient diet and then also fed a deficient diet after birth developed low levels of n-3 fatty acids in the brain and retina and impairment in visual function (Neuringer et al., 1984, Connor et al., 1984, Neuringer et al., 1986). The specific biochemical markers of the n-3-deficient state were a marked decline in the DHA of the cerebral cortex and a compensatory increase in n-6 fatty acids, especially docosapenta-enoic acid (22 5n-6). Thus, the sum total of the n-3 and n-6 fatty acids remained similar, about 50% of the fatty acids in phosphatidylethanolamine and phosphatidylserine, indicating the existence of mechanisms in the brain to conserve polyunsaturation of membrane phospholipids as much as possible despite the n-3-deficient state. 

Using the serial data for the cerebral cortex, plasma, and erythrocytes, we constructed accumulation and decay curves for several key fatty acids in these tissues, which provided gross estimates of their turnover times after fish-oil feeding to n-3 fatty acid-deficient monkeys (Table 2). For cerebral cortex, a steady state was reached after 12 wk of fish-oil feeding for DHA, but 22 5n-6 took longer to decline to the low levels found in the cortex of control animals. The half-lives of DHA in cerebral phospholipids ranged from 17 to 21 d 21 d for phosphatidylethanolamine, 21 d for phosphatidylserine, 18 d for phosphatidylinositol, and 17 d for phosphatidylcholine. The corresponding values for 22 5n-6 in these same phospholipids were 32,49,14, and 28 d, respectively. The half-lives of linoleic acid, EPA, and DHA in plasma phospholipids were estimated to be 8,18, and 29 d, respectively. In the phospholipids of erythrocytes, linoleic acid, arachidonic acids, EPA, and DHA had half-lives of 28, 32, 14, and 21 d, respectively. 

Before 1940 it was generally considered that phosphohpids, once laid down in the nervous system of mammals during growth and development, were comparatively static entities. However, later studies using (32p)oithophosphate showed that brain phospholipids as a whole are metabolically active in vivo (Ansell and Dohmen, 1957, Crokin and Sun, 1978). In the present study, by following the changes in phospholipid fatty acid composition, we have demonstrated that an n-3 fatty acid-enriched diet can rapidly reverse a severe n-3 fatty acid deficiency in the brains of primates. The phospholipid fatty acids of the cerebral cortex of juvenile monkeys are in adynamic state and are subject to continuous turnover under certain defined conditions. 

A comprehensive nutrition assessment must include an evaluation of possible trace element, vitamin, and essential fatty acid deficiencies. Because of their key role in metabolic processes (as coenzymes and cofactors), a deficiency of any of these nutrients may result in altered metabolism and cell dysfunction, and may interfere with metabolic processes necessary for nutritional repletion. The evaluation of single-nutrient-deficiency states includes an accurate history to identify symptoms and risk factors that may indicate deficiency or predispose the patient to developing a deficiency state. A focused physical examination for signs of deficiencies and biochemical assessment to confirm a suspected diagnosis also should be done. Ideally, biochemical assessment would be based on the nutrient s function (e.g., metalloenzyme activity) rather than simply measuring the nutrient s serum concentration. Unfortunately, few practical methods to assess micronutrient function are available currently, and most assays measure serum concentrations of the individual nutrient. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

Long-chain fatty acids are hydrophobic substances in plasma they occur in the esterified state or bound to protein (mainly albumin). As a consequence, long-chain fatty acids are not excreted into the urine and are measured either in the plasma or in erythrocytes, where they are part of the membrane. Erythrocyte levels of polyunsaturated fatty acids (PUFA) are fairly constant and may reliably reflect the longterm availability or deficiency of the essential fatty acids. A list of fatty acids that can be separated and analysed by GC is shown in Table 3.3.1. 

Nutrient deficiencies are difficult to research in humans because the test subject would have to be removed from that nutrient for an extended period of time, possibly to leading a state of starvation. Thus, clinical deficiencies of n-3 fatty acids have been reported by only two researchers. Both of these studies involved one patient each and different clinical symptoms were observed in the patient prior to ALA supplementation (Bjerve et al., 1988 Holman et al., 1982). Thus, our knowledge of symptoms of ALA deficiency is not complete. Furthermore, a complete removal of ALA may not be required for the manifestation of clinical symptoms related to an improper balance between ALA and other fatty acids in the diet. Many of these symptoms can be related to the overproduction of the proinflammatory eicosanoids, synthesized from fatty acids other than ALA, resulting in heart disease and cancer (Morris, 2003b). 

Table VI summarizes total GSH-Px activity toward LHP and 15-HPETE in tissues from rats fed on vitamin E and/or Se deficient diets. GSH-Px activity toward fatty acid hydroperoxides was reduced markedly in liver and lung under Se-deficient states whereas kidney enzyme levels were only marginally affected. It should be noted that these total enzyme activities were contributed by both Se-GSH-Px and non-Se GSH-Px in crude cytosols of Se supplemented animals. However, in Se-deficient...

In the -in vivo situation, the ketogenic action of glucagon is most prominent in states of insulin deficiency. This can be explained because insulin normally suppresses the effect of glucagon on hepatic cAMP levels [170] and inhibits the action of the hormone on lipolysis, i.e., fatty acid release in adipose tissue [171]. 

Glucagon exerts a ketogenic action on the liver which is more pronounced in insulin-deficient states. This action is thought to be due mainly to the inhibition of acetyl-CoA carboxylase with resulting decrease in malonyl-CoA. Malonyl-CoA is an inhibitor of carnitine acyltransferase I which is the rate-limiting step for mitochondrial fatty acid oxidation. A decrease in malonyl-CoA is thus postulated to lead to overproduction of acetyl-CoA which is then condensed to form ketone bodies. 

Our data suggest that the zinc-deficient state may have led to hypercatabolism of fat in our subjects. This is suggested by an Increased fat loss and normal absorption of fat during the zinc restriction phase. In experimental animals an Increase in free fatty acids has been observed as a result of zinc deficiency (17). Indeed, more studies are required in human subjects to document Increased fat catabolism due to zinc restriction. 

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

In diabetes mellitus, blood glucose homoeostasis and rate of lipolysis in adipose tissue appear to be associated. This relationship is most apparent in an insulin-deficient state, where glucose homoeostasis is maintained at the expense of other fuel sources, mainly FFA. Insulin deficiency initiates lipolysis. The increase in fatty acid oxidation further favours hepatic gluconeogenesis. 

With loss of insulin action and an excess of catabolic hormones, hydrolysis of triglycerides is markedly increased, glycerol supply rises and triglyceride turnover in plasma increases with a concomitant increase in ketoacid derived from hepatic oxidation of FFA. Fatty acids are partly oxidized to ketonic compounds. Ketone synthesis increases more than threefold in the state of insulin deficiency as the result of a low insulin/glucagon ratio and a high FFA supply to the liver. At low insulin levels, ketone uptake and utilization of peripheral tissue is also significantly reduced. 

We now realize that deficiencies of 0)3 essential fatty acids are pandemic, especially in modern industrialized societies, and that this is an underlying cause of many burgeoning neurological diseases. The United States of America probably is the current leader in 0)3 deficiencies. How can we reverse the trend Our entire agricultural industry is currently dedicated to the production of crops and products low in o)3 and high o)6... 

Institute of Research (WRAIR, Washington, DC). After finding that a chloroquine-resistant strain of P. berghei was deficient in a high-affinity receptor for the drug (Fitch, 1969,1970), he went on to identify FP as the receptor (Chou et ah, 1980 Fitch et al., 1974) later he found hemozoin to be dimerized FP similar to p-hematin (Fitch and Kanjananggulpan, 1987). Recently, he speculated that unsaturated fatty acids (FAs) and their mono- and diglycerides in the FV serve to concentrate the monomeric FP and keep it in a state favourable for dimerization (Fitch et al., 2003 Fitch and Russell, 2006). 

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