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PubMed1993

Effect of nicotine on cognitive disturbance in animals with acetylcholine deficient brain.

The effect of nicotine on learning disturbance was tested in rats fed with a choline-deficient diet (Ch free) or in senescence-accelerated mice (SAM). Concentration of acetylcholine in the brain was significantly lower in rats fed with Ch free and SAM. Passive avoidance learning shows that rats fed with Ch free and SAM showed significantly impaired learning, compared to controls. Nicotine (0.04 mg/kg) administered intraperitonealy significantly improved learning in animals with learning disturbances, as well as in controls. Vitamin B12 facilitated acetylcholine synthesis or release in the brain and improved the cognitive disturbance. We therefore suggest that acetylcholine contributes to learning and that nicotine may improve learning in an acetylcholine deprived rats.

Acetylcholine↗
PubMed2001

Dietary restriction of choline reduces hippocampal acetylcholine release in rats: in vivo microdialysis study.

We fed rats with a diet deficient in choline for 12 weeks and studied how dietary choline deficiency affected their behavior and their ability to release acetylcholine in discrete regions of rat brain using step-through passive avoidance task and in vivo microdialysis. In comparison with the control, rats fed the choline-deficient diet showed poorer retention of nociceptive memory in the passive avoidance task. Average choline level in cerebrospinal fluid in the choline-deficient group was significantly less (33.1%) than that of control rats. In vivo microdialysis showed no difference in the pattern of acetylcholine release enhanced by intraperitoneal administration of scopolamine hydrochloride (2 mg/kg) in the striatum between the two groups, whereas in the hippocampus, the maximum and subsequent increase of acetylcholine from the baseline by scopolamine injection was significantly lower in the choline-deficient group than in the control. From the results of our study, we speculate that long-term dietary restriction of choline can affect extra- and intracellular sources of substrates required for acetylcholine synthesis, and eventually limit the ability to release acetylcholine in the hippocampus. Reduced capacity to release acetylcholine in the hippocampus implies that the mechanism, maintaining acetylcholine synthesis on increased neuronal demand, may vary in discrete regions of the brain in response to dietary manipulation. The vulnerability of the mechanism in the hippocampus to dietary choline restriction is indicated by impaired mnemonic performance we observed.

Acetylcholine↗
PubMed1989

Choline may be an essential nutrient in malnourished patients with cirrhosis.

Elemental diets designed for nutritional support in protein-calorie malnutrition are often deficient in choline, a nonessential nutrient. Previously, malnourished patients on these diets were found to be at risk of developing plasma choline deficiency. We have now estimated the prevalence of this deficiency by determining fasting plasma levels of choline among cirrhotic and noncirrhotic malnourished male subjects maintained on regular hospital mixed food or elemental parenteral and enteral formulas. Plasma choline concentrations (microM, average +/- SD) were as follows: (i) mixed foods, 11.3 +/- 4.3 for cirrhotic (n = 22) and 9.3 +/- 2.4 for noncirrhotic (n = 12) patients; (ii) parenteral formula, 5.3 +/- 1.6 for cirrhotic (n = 5) and 8.6 +/- 5.2 for noncirrhotic (n = 16) subjects; and (iii) enteral formula, 6.1 +/- 1.2 for cirrhotic (n = 5) and 11.7 +/- 1.9 for noncirrhotic (n = 4) subjects. The level for healthy normal subjects eating mixed foods was 12.0 +/- 2.2. The prevalence of plasma choline deficiency, i.e., plasma levels greater than or equal to 2 SD below the normal average, was as follows: parenteral formula, all cirrhotic and 10 of 16 noncirrhotic subjects; enteral formula, all cirrhotic and none of the noncirrhotic subjects. The reversibility of choline deficiency was examined in a longitudinal study of three phases involving 10 patients--5 with alcoholic cirrhosis (all on enteral formula); 5 noncirrhotic (1 on enteral and 4 on parenteral formula). During phase 1 (3-day equilibration period; ad libitum regular hospital diet), plasma choline levels were within the normal range for all subjects. During phase 2 (2 wk, choline depletion phase, elemental formulas), choline levels were subnormal in all cirrhotic subjects (5.1 +/- 2.0 microM) on enteral formula and all noncirrhotic patients on parenteral formula (5.9 +/- 1.3 microM). During phase 3 (2 wk, choline repletion phase, elemental formula + 6 g choline/day), the levels normalized in all patients (cirrhotic 11.4 +/- 3.1 microM and noncirrhotic 11.9 +/- 3.2 microM). Analyses of abdominal computed tomographic scans and plasma liver chemistries in the cirrhotic subjects during the three phases suggested a correlation between plasma choline deficiency and hepatic steatosis and abnormal liver enzyme levels in some patients. Therefore, choline may be an essential nutrient in malnourished cirrhotic patients and its deficiency may be associated with adverse hepatic effects.

Adult↗
PubMed1984

Effects of chronic manipulations of dietary choline on locomotor activity, discrimination learning and cortical acetylcholine release in aging adult Fisher 344 rats.

Dietary levels of choline have been shown to influence central cholinergic neurotransmission. To further examine the behavioral and neurochemical effects of dietary choline, adult Fisher 344 rats were maintained on choline deficient (n = 6), enriched (n = 6) or usual lab chow (n = 6) diets for 38 weeks. During 14 weeks of free access to these diets, controls gained little weight whereas the deficient group increased and the enriched group decreased. For the remaining 24 weeks the weights of all groups were maintained at 90% of their original level. Locomotor activity did not differ significantly in a 90 min session but during a 20 hr session controls were most active, deficient rats least with the enriched group in between. The groups showed no significant differences in the acquisition or reversal of a discrimination. Spontaneous and evoked cortical release of acetylcholine was enhanced in the enriched group and decreased in the deficient group relative to controls. These data suggest that chronic manipulations of dietary choline may significantly influence locomotor and neurochemical activity but not discrimination learning.

Acetylcholine↗
PubMed2006

Common genetic polymorphisms affect the human requirement for the nutrient choline.

Humans eating diets deficient in the essential nutrient choline can develop organ dysfunction. We hypothesized that common single nucleotide polymorphisms (SNPs) in genes involved in choline metabolism influence the dietary requirement of this nutrient. Fifty-seven humans were fed a low choline diet until they developed organ dysfunction or for up to 42 days. We tested DNA SNPs for allelic association with susceptibility to developing organ dysfunction associated with choline deficiency. We identified an SNP in the promoter region of the phosphatidylethanolamine N-methyltransferase gene (PEMT; -744 G-->C; rs12325817) for which 18 of 23 carriers of the C allele (78%) developed organ dysfunction when fed a low choline diet (odds ratio 25, P=0.002). The first of two SNPs in the coding region of the choline dehydrogenase gene (CHDH; +318 A-->C; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (+432 G-->T; rs12676) was associated with increased susceptibility to choline deficiency. A SNP in the PEMT coding region (+5465 G-->A; rs7946) and a betaine:homocysteine methyltransferase (BHMT) SNP (+742 G-->A; rs3733890) were not associated with susceptibility to choline deficiency. Identification of common polymorphisms that affect dietary requirements for choline could enable us to identify individuals for whom we need to assure adequate dietary choline intake.

Choline↗
PubMed1982

Effect of experimental folate deficiency on lipid metabolism in liver and brain.

1. Rats were given a purified folate-deficient diet containing 5 g succinylsulphathiazole/kg for 4-5 months in two experiments. Control rats were supplemented with folic acid in the drinking-water. 2. Weight gain was much below normal in the folate-deprived rats after the first month. Very low folate levels were recorded in blood, liver and peripheral nerve (12-33% of control). In the central nervous system, including the cerebrospinal fluid, the folate depletion was less conspicuous (50-80% of control). Only marginal signs of anaemia were found and no signs of neurological dysfunction were detected, using nerve conduction velocity measurement and co-ordination tests. 3. Light and electron microscopy of the folate deficient liver revealed fatty infiltration, and enlargement of liver parenchymal cells, nuclei and nucleoli. There was often a considerable amount of bile ductular cells in the lobuli but no cirrhosis. The morphological changes resembled those observed in choline deficiency. 4. Phospholipid N-methylation in liver was depressed in folate-deficiency. This was probably due to a decreased availability of S-adenosylmethionine caused by the low concentrations of methylated folate in liver. Intraperitoneal administration of methionine did not normalize phospholipid methylation. 5. In folate deficiency the proportion of ethanolamine phosphoglyceride in liver was increased at the expense of choline phosphoglyceride, which is consistent with a decreased phospholipid methylation. Also an increase in liver triacylglycerol was noted, in accordance with the morphological observations. Brain lipid composition was unchanged. 6. After the injection of labelled ethanolamine, isotope accumulated in liver phosphoethanolamine in folate deficiency, probably due to an impairment of the CTP:ethanolaminephosphate cytidylyltransferase (EC 2.7.7.14) reaction. The mechanism of this impairment is discussed. 7. Although the low concentrations of folate was the main nutritional change in the deprived animals, changes with respect to vitamin B12 and maybe also choline cannot be excluded. We conclude that some of the changes in folate deficiency, i.e. fatty liver and decreased biosynthesis of liver phospholipids may be due to a precipitated deficiency of lipotropic agents, whereas other differences may be specific for deficiency of folate per se, such as changes in liver phospholipid fatty acids and some of the morphological aberrations.

Animals↗
PubMed1985

Lung surfactant phospholipids as related to hydration and choline status of fasted rats.

Hydration status and choline nutrition were evaluated relative to the concentration of lung surfactant phosphatidylcholine (PC) in fasted rats. Rats deprived of food for 72 h showed lower voluntary water consumption and consistently lower levels of both PC and total phospholipid (TPL) present in isolated pulmonary surfactant than ad libitum-fed controls, although the ratio of surfactant PC to TPL and the residual PC and TPL concentrations were not different. Higher hematocrit values observed in the fasted animals were not altered by the administration of water or saline by orogastric tube nor was the low surfactant PC level corrected by fluid therapy. Evidence of choline deficiency was demonstrated in the fasted rats as there was a significant shift in hepatic PC:phosphatidylethanolamine; however, plasma choline levels did not change. The administration to fasted animals of up to 2.4 mmol of choline chloride via the drinking water (containing 60 mM choline) or an orogastric tube did not affect the plasma choline concentrations or the production of lung surfactant PC.

Animals↗
PubMed2006

The fetal origins of memory: the role of dietary choline in optimal brain development.

Fetal nutrition sets the stage for organ function in later life. In this review we discuss the fetal and neonatal origins of brain function. Numerous research observations point to the importance of choline for the developing fetus and neonate. This essential nutrient is involved in 1-carbon metabolism and is the precursor for many important compounds, including phospholipids, acetylcholine, and the methyl donor betaine. Dietary intake of choline by the pregnant mother and later by the infant directly affects brain development and results in permanent changes in brain function. In rodents, perinatal supplementation of choline enhances memory and learning functions, changes that endure across the lifespan. Conversely, choline deficiency during these sensitive periods results in memory and cognitive deficits that also persist. Furthermore, recent studies suggest that perinatal choline supplementation can reduce the behavioral effects of prenatal stress and the cognitive effects of prenatal alcohol exposure in offspring. The likely mechanism for these effects of choline involves DNA methylation, altered gene expression, and associated changes in stem cell proliferation and differentiation. The currently available animal data on choline and hippocampal development are compelling, but studies are needed to determine whether the same is true in humans.

Brain↗
PubMed1992

Tests of the adaptive modulation hypothesis for dietary control of intestinal nutrient transport.

According to the adaptive modulation hypothesis, an intestinal transporter should be repressed when its biosynthetic and other costs (of maintenance) exceed the benefits it provides. This leads to two contrasting predictions: transport of a sugar or amino acid worth calories should tend to be increased by its substrate, and transport of a vitamin should be modulated downwards by its substrate and upmodulated in deficiency. In a test of the first prediction, omnivorous desert iguanas eating alfalfa pellets (a high-carbohydrate diet) were compared with desert iguanas eating mealworms (a low-carbohydrate, higher-protein diet). In accord with the prediction, intact intestinal sleeves from the former group had higher rates of carrier-mediated D-glucose uptake/centimeter across the brush border than sleeves from the latter group. But in contrast to the first prediction, mealworm eaters had lower (not higher) proline uptake rates, and the ratio of glucose/proline uptake in the two groups did not differ. I review similar tests in 12 other species and show that overall the hypothesis has been quite robust with regard to the first prediction. Cases in which the hypothesis is rejected may reflect complications associated with changes in other dietary factors or phylogenetic constraints. In a test of the second prediction, uptake of the water-soluble vitamin choline was not increased in choline-deficient chicks, nor was it decreased in adults that have no dietary requirement for choline. I review similar tests for four other vitamins and five essential minerals. Dietary control of transport of the minerals and two of the vitamins seems to be in accord with the hypothesis. But transport rate for three vitamins (choline, pantothenic acid, ascorbic acid) seems not to be increased in deficiency. The best explanation seems to be that vitamin transport is modulated only if it is primarily by a carrier-mediated pathway.

Adaptation, Physiological↗
PubMed2002

S-Adenosylmethionine, cytokines, and alcoholic liver disease.

Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.

Animals↗
PubMed1987

A time course and dose-response study of the regulation of brain nicotinic receptors by dietary choline.

We have previously demonstrated that the administration of oral choline chloride to rats results in a significant increase in the concentration of putative nicotinic cholinergic receptors (nAChRs), as measured by alpha-bungarotoxin binding, in comparison with rats fed a choline-free diet. We have extended and elucidated these data in the studies reported here. The increase in the concentration of nAChRs was found to be dose-dependent and attributable to choline supplementation rather than choline deficiency. The increase in the concentration of nAChRs occurs rapidly (within 24 h) and is reversible (over a period of days) upon elimination of choline supplementation. The oral administration of choline chloride had been successful in some but not all neurological disorders associated with presumed cholinergic hypoactivity. Studies of dietary choline intake in animals may provide information with respect to the mechanism by which choline stimulates an increase in nAChRs and may suggest a treatment regime that maximizes the central effects of choline.

Animals↗
PubMed2006

Choline transport for phospholipid synthesis.

Choline is an essential nutrient for all cells because it plays a role in the synthesis of the membrane phospholipid components of the cell membranes, as a methyl-group donor in methionine metabolism as well as in the synthesis of the neurotransmitter acetylcholine. Choline deficiency affects the expression of genes involved in cell proliferation, differentiation, and apoptosis, and it has been associated with liver dysfunction and cancer. Abnormal choline transport and metabolism have been implicated in a number of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therefore, the study of choline transport and the characteristics of choline transporters are of central importance to understanding the mechanisms that underlie membrane integrity and cell signaling in such disorders. Kinetic studies with radiolabeled choline and inhibitors distinguish three systems for choline transport: (i) low-affinity facilitated diffusion, (ii) high-affinity, Na+-dependent transport, and (iii) intermediate-affinity, Na+-independent transport. It is only recently, however, that the proteins having transport characteristics of at least one of these systems have been identified. They include (i) polyspecific organic cation transporters (OCTs) with low affinity for choline, (ii) high-affinity choline transporters (CHT1s), and (iii) intermediate-affinity choline transporter-like (CTL1) proteins. CHT1 and CTL1 but not OCT transporters are selectively inhibited with hemicholinium-3 and essentially display characteristics of specialized transporters for targeted choline metabolism. CHT1 is abundant in neurons and almost exclusively supplies choline for acetyl-choline synthesis. The focus here is more on newly-discovered CTL1 choline transporters. They are expressed in different organisms and cell types, apparently not for the biosynthesis of acetylcholine but for the production of the most abundant metabolite of choline, the membrane lipid phosphatidylcholine.

Amino Acid Sequence↗
PubMed1992

Stimulation of sphingomyelin biosynthesis by brefeldin A and sphingomyelin breakdown by okadaic acid treatment of rat hepatocytes.

Studies on sphingomyelin metabolism in rat hepatocytes were facilitated by the use of choline-deficient cells which allowed for the rapid labeling of phosphatidylcholine and as a result sphingomyelin. Pulse and pulse-chase studies with [methyl-3H]choline and [methyl-3H]methionine demonstrated that both compounds were effectively used for sphingomyelin biosynthesis and that newly made and pre-existing phosphatidylcholine could be used for sphingomyelin biosynthesis. When hepatocytes were incubated with brefeldin A, there was a 2.4-fold stimulation of the conversion of phosphatidylcholine into sphingomyelin. Since brefeldin A causes collapse of the cis/medial Golgi into the endoplasmic reticulum the stimulation of sphingomyelin biosynthesis could be due to more rapid access of the labeled phosphatidylcholine in the endoplasmic reticulum to sphingomyelin synthase in the collapsed Golgi. Forskolin inhibited the brefeldin A-induced stimulation of sphingomyelin biosynthesis. To investigate whether or not phosphorylation reactions regulate sphingomyelin metabolism, hepatocytes were incubated with okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A. Rather than stimulating sphingomyelin biosynthesis, okadaic acid enhanced the catabolism of sphingomyelin. In contrast, a cyclic AMP analogue and forskolin had no effect on sphingomyelin biosynthesis or catabolism. Surprisingly, other pulse-chase studies demonstrated that okadaic acid stimulated the catabolism of only newly made sphingomyelin. The brefeldin A and okadaic acid effects were independent of lysosomal involvement. Subcellular fractionation studies revealed that brefeldin A and okadaic acid effects were generalized in all sphingomyelin containing membranes. The brefeldin A studies suggest that the rate of transfer of phosphatidylcholine from the endoplasmic reticulum to the Golgi might be limiting for sphingomyelin biosynthesis. The okadaic acid studies indicate that the catabolism of sphingomyelin by a sphingomyelinase is regulated by an unidentified protein kinase and by either protein phosphatase 1 and/or 2A activity in hepatocytes.

Animals↗
PubMed1992

Choline: an important nutrient in brain development, liver function and carcinogenesis.

Choline is required to make certain phospholipids which are essential components of all membranes. It is a precursor for biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Much attention has been given to the effect of supplemental choline upon brain function, i.e., enhancement of acetylcholine synthesis and release. In addition, choline supplements administered to rats in utero or shortly after birth permanently after brain function. The mechanisms for this effect is unknown and under investigation at this time. Healthy humans fed diets deficient in choline, and humans fed parenterally have decreased plasma choline concentrations and develop liver dysfunction that is similar to that seen in choline-deficient animals. In experimental animals, fatty liver occurs in choline deficiency because phosphatidylcholine synthesis is required for very low-density lipoprotein secretion. This accumulation of lipids in liver may explain why choline-deficient rats spontaneously develop hepatocarcinoma. We found that choline deficiency was associated with the accumulation of 1,2-diacylglycerol, an activator of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction.

Alanine Transaminase↗
PubMed1986

A choline-devoid diet, carcinogenic in the rat, induces DNA damage and repair.

A diet deficient in choline when fed to rats for as few as 3 days resulted in liver DNA damage. The damage could be monitored as alkali-labile lesions using alkaline-sucrose gradients as well as alkaline elution technique. The DNA damage disappeared when the choline-deficient diet was replaced by a choline-supplemented diet suggesting the alkali-labile lesions were repairable. The DNA damage was detected at a time when no liver cell death was detectable. The induction of DNA damage in a proliferating liver by the choline-deficient diet may be an early important event leading to initiation of liver carcinogenesis.

Animals↗
PubMed1995

An in vivo 31P magnetic resonance spectroscopy study of uridine excess in rats fed orotic acid.

Spatially localized 31P NMR spectroscopy was used to assay in vivo the liver of intact rats fed orotic acid (OA) in a diet which produces hepatic steatosis. Twenty-three sets of multiple volume spectra were obtained from twenty-one 265- to 315-g female rats after 0-9 days of feeding either a 1% OA/64% sucrose diet (12 rats) or a 65% sucrose control diet (9 rats). The intensity of the in vivo diphosphodiester resonance ascribed to UDP-hexos(amin)es increased and the phosphomonoester resonance decreased in intensity prior to fatty infiltration. High resolution NMR spectroscopy of extracts of these livers indicated that the UDP-hexos(amin)e peak included four different UDP-sugars including UDP-N-acetylglucosamine (UDP-glcNAc), and that lower phosphocholine (P-Cho) accounted for the lower phosphomonoester resonance in vivo. Increased UDP-glcNAc is thought to reflect impaired lipoprotein glycosylation as a mechanism for hepatic steatosis in orotic acid feeding. P-Cho deficiency has been shown to be due to an increased rate of phosphatidylcholine synthesis. Low P-Cho concentration has been shown to be associated with lipid accumulation in a choline-deficient diet, but was not previously associated with hepatic steatosis in OA feeding. Changes in phosphorus metabolites were observed 2 days prior to development of fatty liver. HPLC assay of uridine nucleotides showed a good correlation between magnetic resonance spectroscopy and HPLC quantitation. In this study there were two biochemical correlates of impaired hepatic lipid secretion detectable by in vivo assay with 31P NMR spectroscopy. This method has application for noninvasive assays in ornithine transcarbamylase-deficient patients.

Animals↗
PubMed1987

Novel approaches to the pathophysiology of heatstroke: the energy depletion model.

De-emphasis of the role of anhydrosis as the primary cause of heatstroke has resulted in increased usage and acceptance of animal models for heatstroke research. When the total amount of work achieved by the running rat prior to exhaustion was plotted against the rate of heat storage, a heretofore unrecognized relationship emerged. These new data suggest that physical exhaustion and heat exhaustion represent opposite ends of a continuum related to the rate of heat storage. Changes in thermoregulatory and/or physical performance can be estimated by a two-dimensional shift in the work-output/thermal storage ratio. Potassium depletion reduces thermoregulatory/physical performance; a combination of atropine plus diazepam appears to improve it. The role of the cholinergic nervous system in eliciting alterations in thermoregulatory and physical ability is reviewed; endurance training, shivering, acclimatization, set-point theory, the anticholinergic syndrome, lithium intoxication, and choline deficiency are discussed.

Adaptation, Physiological↗