Induction of threonine imbalance by dispensable amino acids: relation to competition for amino acid transport into brain.

The ability of low protein diets containing small neutral, dispensable amino acids to induce threonine imbalance has been examined. Diets containing amino acids which compete for threonine transport in vitro (serine, alanine, alpha-amino-n-butyrate) caused depressions of growth and food intake which could be corrected to varying degrees by adding threonine to the diet. Large neutral, indispensable amino acids, moderately inhibitory of threonine transport, also induced the imbalance. Some amino acids that had little or no effect on threonine transport in vitro (acidic amino acids and proline) did not cause growth and food intake depressions. Other non-inhibitory amino acids (arginine and lysine) caused growth depressions which were not satisfactorily corrected by additional threonine alone, but were prevented by supplements of all the indispensable amino acids including threonine. Ornithine which was also not inhibitory of threonine transport was an exception. It induced a moderate growth depression which was corrected by additional threonine. Similar studies showed that histidine or tryptophan imbalance could be induced by feeding diets containing only those large neutral amino acids which compete for histidine or tryptophan transport in vitro. These experiments show that, based on the results of transport competition experiments, it is generally possible to devise amino acid supplements which can induce a dietary imbalance of a given amino acid.     

Induction in rats of lysine imbalance by dietary homoarginine

The use of dietary homoarginine (HA) to produce a lysine imbalance was examined in young rats. HA, a basic amino acid analogue, was shown earlier to compete with lysine for transport across the blood-brain barrier. Feeding a diet limiting in lysine and containing HA reduced food intake and growth; increasing dietary lysine content lessened these effects. A 3-fold increase in dietary lysine caused 10, 4, 20 and 50-fold increases in lysine concentrations in plasma, brain, liver and muscle, respectively, and reductions in ornithine concentration of brain and liver and in arginine concentration of brain. HA increased lysine levels in plasma, liver and muscle of rats fed the lysine-limiting control diet, but lysine concentrations were reduced by HA when dietary lysine was high. HA invariably lowered concentrations of lysine, ornithine and arginine in brain and ornithine concentrations in plasma and muscle. Brain concentrations of small and large neutral amino acids were unchanged by HA; an exception was glycine, which was high in the brains of rats fed HA. The HA-associated, selective reductions in levels of each basic amino acid in brain in the ratios of these concentrations to those in plasma support the concept that effects of an amino acid imbalance involve competition for amino acid entry into the brain from the blood.     

Dietary lysine and carnitine: relation to growth and fatty livers in rats.

Male weanling rats were fed a 72% rice diet containing no detectable carnitine and limiting in threonine and lysine. Such dietary conditions may simulate protein malnutrition in man. Under these conditions growth impairment, anemia, hypoproteinemia, and fatty liver developed. The study focused principally on the fatty liver syndrome which was corrected to varying extents depending on degrees of supplementation with carnitine, lysine, threonine, and appropriate combinations of these nutrients. Such reduction in fatty liver accumulation was accounted for principally by the lowering of triglycerides, but also in part of total cholesterol levels. All the data, which also included monitoring carnitine uptake by the tissues and measurement of plasma triglycerides, were consistent with the view that fatty liver accumulation occurs in amino acid deficient diets because (a) of an impairment in the synthesis of the lipoprotein complex mandatory for triglyceride secretion from the liver and (b) from a deficiency of carnitine needed for the intramitochondrial transport of fatty acids prerequisite for their oxidation.     

In vitro intestinal lead uptake and transport in relation to speciation

Children might be exposed substantially to contaminants such as lead via soil ingestion. In risk assessment of soil contaminants there is a need for information on oral bioavailability of soilborne lead. Oral bioavailability can be seen as the result of four steps: (1) soil ingestion; (2) mobilization from soil during digestion, i.e., bioaccessibility; (3) transport across the intestinal epithelium; and (4) first-pass effect. Lead bioaccessibility and speciation in artificial human small intestinal fluid, i.e., chyme, have been investigated in previous studies. In the present study, transport of bioaccessible lead across the intestinal epithelium was investigated using the Caco-2 cell line. Cell monolayers were exposed to (diluted) artificial chyme. In 24 h, approximately 27% of the lead were associated to the cells and 3% were transported across the cell monolayer, without signs of approaching equilibrium. Lead associated to the cells showed a linear relationship with the total amount of lead in the system. Bile levels did not affect the fraction of lead associated to Caco-2 cells. Extrapolation of the lead flux across the Caco-2 monolayer to the in vivo situation indicates that only a fraction of the bioaccessible lead is transported across the intestinal epithelium. Furthermore, the results indicate that as the free Pb(2+) concentration in chyme was negligible, lead species other than the free metal ion must have contributed to the lead flux toward the cells. On the basis of lead speciation in chyme, this can be attributed to dissociation of labile lead species, such as lead phosphate and lead bile complexes, and subsequent transport of the released free metal ions toward the intestinal membrane.     

Dietary amino acid analogues and transport of lysine or valine across the blood-brain barrier in rats

Studies were undertaken to determine if dietary disproportions of amino acids would alter flux into brain of the amino acid present in the diet in a growth-limiting concentration. Rats were adapted to a lysine-limiting diet before receiving a meal of this control diet, alone or with added lysine or homoarginine (a competitor for lysine transport) or both, before intravenous infusion of [14C]lysine. The brain-to-plasma radioactivity ratio was lower in rats fed extra lysine or homoarginine than in rats fed the control diet, whereas lysine flux and brain lysine concentration were high in rats fed extra lysine alone. Flux and concentration were lower in rats fed homoarginine + lysine than in rats fed extra lysine alone. Other rats were fed a valine-limiting diet containing added valine, norleucine (a competitor for valine transport) or both, before [14C]valine was infused. Valine flux and brain valine concentrations were higher in rats fed extra valine than in control rats, whereas flux was lower in the group fed norleucine alone. Valine flux was higher in rats fed norleucine + valine than in the rats fed norleucine alone. Our studies show that dietary disproportions of amino acids can alter the flux of specific amino acids across the blood-brain barrier.     

In vitro kinetics of the intestinal transport of riboflavin in rats

Transmural intestinal transport of riboflavin was studied in a concentration range between 0.033 and 10.0 microM by an in vitro perfusion technique by using everted jejunal segments of rats. The transport was found to have a dual characteristic: at low, i.e., physiologically relevant concentrations, a carrier-mediated saturable component predominated; at higher concentrations this component was increasingly obscured by simple diffusion as the prevailing transport mechanism. The transport constant KT of the saturable component was calculated to be 0.54 microM. The Q10-value was 2.31 for a low concentration (0.322 microM) and 1.44 for a high concentration (10.0 microM) of the substrate. When Na+ was partially replaced by Li+ or choline+ in the media or when ouabain was added to the serosal medium, the saturable component of the transport was completely abolished. The substrate analogue lumiflavin reduced the transport rate of riboflavin at low substrate concentration only. Generally, the results indicate that it is essential to consider the physiologically relevant concentration of micronutrients in studies concerning the mechanism of their intestinal transport.     

Manganese and copper imbalance in the food chain constituents in relation to Creutzfeldt-Jakob disease

The objective of the study was to investigate the possible role of manganese and copper (Mn/Cu) imbalance of the food chain in the focally increased occurrence of Creutzfeldt-Jakob disease (CJD). Mn and Cu concentrations in soil, drinking water and foodstuffs collected from households in the region of focal accumulation of CJD patients and the control region were measured by FAAS. Considerably higher Mn/Cu ratios in the studied region than those in the control region were found for soil (49.3 vs. 21.1), honey (8.05 vs. 4.86), and for the main local food items: potatoes (2.09 vs. 1.07) and bread (5.85 vs. 5.35), however, only soil and potatoes were of statistical significance. The results could indicate a rare coincidence of the verified endogenous CJD risk (genetic) with a very probable exogenous CJD risk factor (Mn/Cu dietary/environmental imbalance), but whether and how this coincidence may contribute to the unique, continual temporo-spatial clustering of genetic CJD should be investigated in further studies.     

The transport of 57Co-B12 from plasma into brain of 6-hydroxydopa treated rats: Implications for the use of vitamin B12 therapy in Alzheimer's Dementia

It has been suggested that the deficient vitamin B₁₂ transport into brain tissue which is commonly observed in patients with Alzheimer's Dementia is produced by deficient noradrenergic neurotransmission. To determine the effects of central noradrenergic depletion on the transport of vitamin B₁₂ into brain tissue, rats were injected (i.p.) with ⁵⁷Co labelled vitamin B₁₂ several days after their central noradrenergic neurons were destroyed with injections of 6-hydroxydopa. Pretreatment with this neurotoxin did not alter the passage of ⁵⁷Co-B₁₂ into the brain, and we conclude that the noradrenergic/vitamin B₁₂ transport mechanism is not of primary significance in Alzheimer's Dementia. Other mechanisms involving impaired microsomal liver enzyme function may be more important in the aetiology of Alzheimer's Dementia.     

Structured form of DHA prevents neurodegenerative disorders: A better insight into the pathophysiology and the mechanism of DHA transport to the brain

Docosahexaenoic acid (DHA) is one of the most important fatty acids that plays a critical role in maintaining proper brain function and cognitive development. Deficiency of DHA leads to several neurodegenerative disorders and, therefore, dietary supplementations of these fatty acids are essential to maintain cognitive health. However, the complete picture of how DHA is incorporated into the brain is yet to be explored. In general, the de novo synthesis of DHA is poor, and targeting the brain with specific phospholipid carriers provides novel insights into the process of reduction of disease progression. Recent studies have suggested that compared to triacylglycerol form of DHA, esterified form of DHA (i.e., lysophosphatidylcholine [lysoPC]) is better incorporated into the brain. Free DHA is transported across the outer membrane leaflet of the blood-brain barrier via APOE4 receptors, whereas DHA-lysoPC is transported across the inner membrane leaflet of the blood-brain barrier via a specific protein called Mfsd2a. Dietary supplementation of this lysoPC specific form of DHA is a novel therapy and is used to decrease the risk of various neurodegenerative disorders. Currently, structured glycerides of DHA – novel nutraceutical agents – are being widely used for the prevention and treatment of various neurological diseases. However, it is important to fully understand their metabolic regulation and mechanism of transportation to the brain. This article comprehensively reviews various studies that have evaluated the bioavailability of DHA, mechanisms of DHA transport, and role of DHA in preventing neurodegenerative disorders, which provides better insight into the pathophysiology of these disorders and use of structured DHA in improving neurological health.