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PubMed1997

Phosphatidylcholine biosynthesis is required for secretion of truncated apolipoprotein Bs from McArdle RH7777 cells only when a neutral lipid core is formed.

Decreased phosphatidylcholine biosynthesis inhibits the secretion of very low density lipoproteins from hepatocytes (Yao, Z. and D. E. Vance. 1988. J. Biol. Chem. 263: 2998-3004). We have now investigated whether or not phosphatidylcholine biosynthesis is required for secretion of carboxyl-truncated apoBs 15, 18, 23, 28, and 37 from transfected McArdle RH7777 cells. Transfected cells were choline-deprived for 1 day and then choline-supplemented or maintained choline-deficient. Pulse-chase experiments showed that in the presence of 100 microM choline, the secretion of apoBs 28 and 37 was increased by up to 50 and 45%, respectively, whereas the secretion of apoBs 15, 18, and 23 was not affected by the addition of choline. Immunoblot analyses also showed that choline in the medium increased the secretion of apoBs 28 and 37 by 30-50% whereas the secretion of apoBs 15, 18, and 23 was unaffected over 24 h. As only carboxyl-terminal truncations with a size greater than 23% of apoB-100 are able to assemble a neutral lipid core (McLeod, R. S., Y. Zhao, S. L. Selby, J. Westerlund, and Z. Yao. 1994. J. Biol. Chem. 269: 2852-2862), we conclude that only apoB-truncations that assemble a neutral lipid core require phosphatidylcholine synthesis. Other experiments established that the requirement of phosphatidylcholine for apoB secretion is related to the presence of neutral lipid associated with a truncation, rather than the length of apoB.

Animals↗
PubMed1989

Genetic control of susceptibility to diethylnitrosamine carcinogenesis in inbred ACP (grc+) and R16 (grc) rats.

The R16 strain, which carries the major histocompatibility complex-linked growth and reproduction complex (grc), and its normal counterpart, the ACP strain, were initiated at 8 wk of age with a single i.p. dose of diethylnitrosamine (DEN), and 2 wk later they were fed either a choline-deficient (CD) or a choline-supplemented (CS) diet. The rats were sacrificed 2, 4, 6, 10, and 12 mo later; complete autopsies were performed, and all of the tissues were examined histologically. Sections of the liver were also examined histochemically for gamma-glutamyl transpeptidase activity. Shortly after the administration of DEN, the R16 strain showed a significant increase in the number and size of gamma-glutamyl transpeptidase-positive foci and more severe histological changes (disruption of the lobular architecture, bile duct and oval cell proliferation, cellular atypia, and accumulation of fat) compared with the ACP strain. These changes occurred in animals fed either CD or CS diet, but they were much more extensive and severe in the animals on the CD diet. They did not occur in rats of either strain fed the diets alone. The first hepatocellular carcinoma appeared in the R16 rats on the CD diet at 4 mo after administration of the DEN and on the CS diet, at 10 mo. The only hepatocellular carcinoma that occurred in the ACP rats did so at 12 mo in one animal on the CD diet. Combining the data at 10 and 12 mo for the rats on the CD diet, 50% (20 of 40) of the R16 rats had hepatocellular carcinomas, whereas only 3% (one of 30) of ACP rats did. The R16 strain (22%, 9 of 40), but not the ACP strain (0 of 30), also had a variety of other malignancies: squamous cell carcinomas (8%); renal cell carcinomas (8%); lymphomas (5%); and pheochromocytoma (3%). A similar pattern of malignancies also occurred in the R16 rats on the CS diet, and there were no malignancies in the ACP rats. These observations indicate that the grc confers unusual susceptibility to the induction of cancer by the chemical carcinogen DEN and that this genetic susceptibility to cancer of the R16 strain extends beyond the primary target organ of the carcinogen used.

Animals↗
PubMed1976

Deuterium magnetic resonance spectroscopy of isotopically labeled mammalian cells.

Choline completely deuterated in the methyl groups has been incorporated into two mammalian cell systems. The first was the chemically transformed mouse fibroblast LM cell line, grown in suspension culture. The second system consisted of mitochondria from Sprague-Dawley rats which were fed upon a choline-deficient diet enriched with deuterated choline chloride. Two classes of deuterium nuclear magnetic resonance (NMR) signal were obtained from each system. The first class of signal exhibited no residual quadrupole coupling constant and was assigned to the natural abundance of 2H in water, together with free labeled choline. The second class of signal had a residual quadrupole coupling of about 1 HKz and was assigned to 2H-labeled choline headgroups of phospholipids. These results are in conflict with a previous study of deuterated rat liver mitochondrial membranes. Deuterium magnetic resonance spectra can be obtained on mammalian membranes that have incorporated specific deuterium-labeled compounds and, therefore, provides a very powerful method for studying the dynamic structure of membranes.

Animals↗
PubMed1998

Prenatal dietary choline supplementation decreases the threshold for induction of long-term potentiation in young adult rats.

Choline supplementation during gestation in rats leads to augmentation of spatial memory in adulthood. We hypothesized that prenatal (E12-E17) choline supplementation in the rat would lead to an enhancement of hippocampal synaptic plasticity as assessed by long-term potentiation (LTP) at 3-4 mo of age. LTP was assessed blindly in area CA1 of hippocampal slices with first suprathreshold (above threshold for LTP generation in control slices) theta-burst stimulus trains. The magnitude of potentiation after these stimuli was not different between slices from control and prenatally choline supplemented animals. Next, threshold (reliably leading to LTP generation in control slices) or subthreshold theta-burst stimulus trains were applied to slices from control, prenatally choline-supplemented, and prenatally choline-deprived rats. Threshold level stimulus trains induced LTP in slices from both the control and choline-supplemented rats but not in those from the choline-deficient rats. Subthreshold stimulus trains led to LTP induction in slices from prenatally choline-supplemented rats only. These observations indicate that prenatal dietary manipulation of the amino acid, choline, leads to subsequent significant alterations of LTP induction threshold in adult animals.

Animals↗
PubMed1986

DNA methylation and hepatocarcinogenesis in rats fed a choline-devoid diet.

Groups of male Fischer-344 rats were fed either a choline-supplemented or a choline-devoid (CD) diet, for up to 14 months. In rats fed the CD diet, hepatic lesions developed and progressed through two distinct stages, the first characterized by severe steatosis and an increase in cell turnover and the second by gradual clearance of the deposited fat, fibrosis and parenchymal nodularity. Large hepatocellular carcinomas were found in rats killed at 14 months. DNA was purified from the livers of all groups of rats and from the tumors, and its level of methylation was analyzed using the restriction endonucleases HpaII and MspI. DNA undermethylation was detected only in the livers of rats fed the CD diet for 14 months, whether bearing tumors or not, and in three of four hepatocellular carcinomas. Undermethylation of liver total DNA is therefore a late effect of dietary choline deficiency in the rat.

Animals↗
PubMed1994

Choline and human nutrition.

Choline is crucial for sustaining life. It modulates the basic signaling processes within cells, is a structural element in membranes, and is vital during critical periods in brain development. Choline metabolism is closely interrelated with the metabolism of methionine and folate. We believe that the normal human diet provides sufficient choline to sustain healthy organ function. However, vulnerable populations may become choline deficient, including the growing infant, the pregnant or lactating woman, the cirrhotic, and the patient fed intravenously. Further studies of choline requirements in these groups are required.

Animals↗
PubMed2000

Increased uracil misincorporation in lymphocytes from folate-deficient rats.

The development of certain human cancers has been linked with inadequate intake of folates. The effects of folate deficiency in vivo on DNA stability (strand breakage, misincorporated uracil and oxidative base damage) in lymphocytes isolated from rats fed a diet deficient in folic acid was determined. Because the metabolic pathways of folate and other methyl donors are closely coupled, the effects of methionine and choline deficiency alone or in combination with folate deficiency were determined. Feeding male Hooded Lister rats a folate-free diet for 10 weeks created a moderate folate deficiency (25-50% (approx.) decrease in plasma, red blood cell and hepatic folate concentrations (P < 0.05) and a 20% rise in plasma homocysteine (P < 0.05)). Lymphocyte DNA strand breakage was increased successively in all groups after 4 weeks and 8 weeks on the diet (50-100% (approx.) after 8 weeks). Only low folate specifically and progressively induced uracil misincorporation throughout the study (100% (approx.) after 8 weeks). Neither folate deficiency nor choline/methionine deficiency altered oxidative DNA base damage. In summary, moderate folate deficiency in vivo is associated with a decrease in DNA stability, measured as increased DNA strand breakage and misincorporated uracil.

Animals↗
PubMed1978

Effects of dietary choline and N,N-dimethylaminoethanol on lung phospholipid and surfactant of newborn rats.

Pups delivered by rats fed during pregnancy a choline-deficient (CD) diet containing 1% N,N-dimethylaminoethanol (DME) die within 36 hr of birth. The concentrations of sphingomyelins, phosphatidyl cholines, and disaturated phosphatidyl cholines in the lungs of these pups are lower than those in the lungs of pups delivered by dams fed a choline-supplemented diet (CS). The amount of surfactant isolated from the lung of the pups was also reduced. These changes were accompanied by alterations in the activity of enzymes (choline kinase, EC 2.7.1.32; choline phosphotransferase, EC 2.7.8.2) involved in the synthesis of lung lecithins. These results strongly suggest that pups delivered by dams fed a CD diet containg 1% DME die of respiratory distress syndrome due to altered metabolism of lung surfactant.

Animals↗
PubMed2005

Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice.

BACKGROUND: While tumour necrosis factor alpha (TNF-alpha) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood. METHODS: Male mice deficient in both TNF receptors 1 (TNFR1) and 2 (TNFR2) (TNFRDKO mice) and wild-type mice were fed a methionine and choline deficient (MCD) diet or a control diet for eight weeks, maintaining isoenergetic intake. RESULTS: MCD dietary feeding of TNFRDKO mice for eight weeks resulted in attenuated liver steatosis and fibrosis compared with control wild-type mice. In the liver, the number of activated hepatic Kupffer cells recruited was significantly decreased in TNFRDKO mice after MCD dietary feeding. In addition, hepatic induction of TNF-alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 was significantly suppressed in TNFRDKO mice. While in control animals MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in both whole liver and hepatic stellate cells, concomitant with enhanced activation of hepatic stellate cells, both factors were significantly lower in TNFRDKO mice. In primary cultures, TNF-alpha administration enhanced TIMP-1 mRNA expression in activated hepatic stellate cells and suppressed apoptotic induction in activated hepatic stellate cells. Inhibition of TNF induced TIMP-1 upregulation by TIMP-1 specific siRNA reversed the apoptotic suppression seen in hepatic stellate cells. CONCLUSIONS: Enhancement of the TNF-alpha/TNFR mediated signalling pathway via activation of Kupffer cells in an autocrine or paracrine manner may be critically involved in the pathogenesis of liver fibrosis in this NASH animal model.

Animals↗
PubMed1982

Influence of dietary protein and excess methionine on choline needs for young bobwhite quail.

Experiments were conducted with young Bobwhite quail (Colinus virginianus) to investigate the effect of differing dietary protein levels and nondetrimental amounts of excess methionine on choline needs. Growth and feed consumption of quail fed an adequate (27.3%) protein purified diet supplemented with 2000 mg/kg of choline were unaffected by increasing the level of excess methionine to 1.75%; however, greater amounts (2.0%, 2.25%) of excess methionine depressed growth (P less than .01), reduced feed consumption (P less than .01), and decreased feed utilization (P less than .05). Quail fed a purified diet containing 13.85% protein and 515 mg/kg of choline grew poorly. Growth was unaffected by additional choline in this diet. Growth was suboptimal among quail fed purified diets containing adequate or high (41.55%) levels of protein in which choline was limiting; however, a high level of protein did not in itself affect performance. Growth was improved by supplemental choline in these diets. Growth of quail fed purified diets with up to 1.35% excess methionine which were limiting (531 mg/kg) in choline was less than that of groups fed 2000 mg/kg of added dietary choline (P less than .01); however, excess methionine did not significantly influence growth of quail fed choline-deficient diets. These experiments indicate that neither high dietary protein nor excess methionine, fed at non-growth-depressing levels, increases dietary choline needs for young Bobwhite quail.

Animals↗
PubMed1995

Axonal synthesis of phosphatidylcholine is required for normal axonal growth in rat sympathetic neurons.

The goal of this study was to assess the relative importance of the axonal synthesis of phosphatidylcholine for neurite growth using rat sympathetic neurons maintained in compartmented culture dishes. In a double-labeling experiment [14C]choline was added to compartments that contained only distal axons and [3H]choline was added to compartments that contained cell bodies and proximal axons. The specific radioactivity of labeled choline was equalized in all compartments. The results show that approximately 50% of phosphatidylcholine in distal axons is locally synthesized by axons. The requirement of axonal phosphatidylcholine synthesis for neurite growth was investigated. The neurons were supplied with medium lacking choline, an essential substrate for phosphatidylcholine synthesis. In the cells grown in choline-deficient medium for 5 d, the incorporation of [3H]palmitate into phosphatidylcholine was reduced by 54% compared to that in cells cultured in choline-containing medium. When phosphatidylcholine synthesis was reduced in this manner in distal axons alone, growth of distal neurites was inhibited by approximately 50%. In contrast, when phosphatidylcholine synthesis was inhibited only in the compartment containing cell bodies with proximal axons, growth of distal neurites continued normally. These experiments imply that the synthesis of phosphatidylcholine in cell bodies is neither necessary nor sufficient for growth of distal neurites. Rather, the local synthesis of phosphatidylcholine in distal axons is required for normal growth.

Animals↗
PubMed1982

Dietary choline augments blood choline and cholinergic transmission in terrestrial mollusk Limax maximus.

1. A radioenzymatic assay was used to determine the concentration of choline in the hemolymph of the terrestrial mollusk Limax maximus maintained on choline-enriched and choline-deficient diets. The levels of free choline in the slug's hemolymph varied with the availability of choline in the diet. The concentration of choline in the plasma of choline-enriched animals averaged 5.5 microM while the mean circulating choline level of choline-deprived slugs was 3.3 microM. The difference in choline levels between the two groups was statistically significant. 2. Neurophysiological measurements of transmission at the isolated cholinergic synapses between the salivary burster neuron (SB) and the salivary duct muscle (SD) showed that this synapse was sensitive to fluctuations in the external choline concentration within the physiological range. Increases in exogenous choline from 0.5 to 2.0 microM, from 2.5 to 5.0 microM, and from 5.0 to 15.0 microM were followed by increases in the amplitudes of SB-elicited junction potentials recorded from the SD by a focal extracellular electrode. 3. Thus, the SB-SD synapse is sensitive to the fluctuations in exogenous choline that can occur with a change in diet.

Acetylcholine↗
PubMed2005

Hyperhomocysteinemia and arteriosclerosis: historical perspectives.

Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915-1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Animals↗
PubMed1985

Phosphorylation of specific rat plasma membrane proteins during promotion of gamma-glutamyl transpeptidase-positive hepatic foci and inhibition by di(2-ethylhexyl)phthalate.

The protein kinase activity of isolated plasma membranes from the livers of rats treated with three promoting regimens was examined using both exogenous proteins and endogenous plasma membrane proteins as substrates. Male rats first received either an initiating dose (30 mg/kg) of the hepatocarcinogen diethylnitrosamine or the 0.9% NaCl solution vehicle by i.p. injection at 18 h following partial hepatectomy. Ten days later, the three promoting regimens were begun. These consisted of 10 weeks of treatment with either (a) a choline-deficient (CD) diet, (b) a choline-supplemented (CS) diet containing 0.06% phenobarbital (PHB) (CS plus PHB), or (c) a CD diet containing 0.06% PHB (CD plus PHB). In addition, two other groups of rats received either (a) a CS diet containing 2% di(2-ethylhexyl)phthalate (DEHP) (CS plus DEHP) or (b) a CD diet containing 2% DEHP (CD plus DEHP). DEHP is a widely used plasticizer and environmental contaminant which we have shown previously inhibits the development of putative preneoplastic gamma-glutamyl transpeptidase (GGT) positive foci in rat liver. Total liver plasma membrane protein kinase activity using both protamine sulfate and histone was cyclic adenosine 3':5'-monophosphate independent and did not appear to be a marker of promotion. Its activity was increased by both DEHP which suppresses the development of GGT positive foci and a CD diet which promotes the appearance of GGT positive foci. The CD, CS plus PHB, and CD plus PHB dietary regimens, which promote the appearance of GGT positive foci, induced the phosphorylation of a Mr 40,000 plasma membrane protein in vitro by endogenous protein kinases. Plasma membranes from DEHP-treated rats did not demonstrate phosphorylation of this Mr 40,000 protein. DEHP dietary treatment also blocked the ability of epidermal growth factor to enhance the phosphorylation of its Mr 175,000 receptor protein in isolated liver plasma membranes. These results suggest that the phosphorylation of a Mr 40,000 plasma membrane protein may be important to the early promotional phase of liver carcinogenesis, and that one mechanism by which DEHP inhibits the emergence of GGT positive foci may be by blocking the response of initiated cells to stimulation by epidermal growth factor.

Animals↗
PubMed2002

Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice.

Several epidemiological studies have suggested a modulatory effect of dietary folate intake on the risk of colorectal cancer. The molecular basis for this inverse association is not clearly understood, but may involve alterations in DNA methylation. In this study, we examined the levels of methylation intermediates [S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)] and of global DNA methylation in the pre-neoplastic small intestine of Min (multiple intestinal neoplasia) mice. We also studied the effect of folate/choline deficiency on these parameters and on tumor multiplicity in this animal model. In folate-adequate Min mice, we identified positive linear correlations between SAM or SAH and tumor numbers (R(2) = 0.38, P < 0.005; R(2) = 0.26, P = 0.025, respectively). A positive correlation between global DNA hypomethylation and tumor multiplicity was also observed (R(2) = 0.29, P = 0.014). These three biochemical determinants (SAM, SAH and DNA hypomethylation) may, therefore, serve as early markers of cell transformation. Folate/choline deficiency, however, did not produce a consistent effect on tumor numbers in three separate experiments. As an increase in tumor numbers was observed only in folate- and choline-deficient mice with low levels of SAM and DNA hypomethylation, the modulatory role of folate may be dependent on the transformation state of the cell.

Animals↗
PubMed2006

Effects of iron overload in a rat nutritional model of non-alcoholic fatty liver disease.

BACKGROUND/AIMS: This study sought to determine whether excess hepatic iron potentiates liver injury in the methionine choline-deficient (MCD) model of non-alcoholic fatty liver disease (NAFLD). METHODS: Iron-loaded rats were fed either MCD or control diets [MCD diet plus choline bitartrate (2 g/kg) and DL-methionine (3 g/kg)] for 4 and 12 weeks, after which liver pathology, hepatic iron, triglyceride, lipid peroxidation products and hydroxyproline (HYP) levels and serum alanine aminotransferase (ALT) levels were evaluated. RESULTS: Iron supplementation in MCD animals resulted in histologic evidence of hepatic iron overload at 4 and 12 weeks and a 14-fold increase in hepatic iron concentration at 12 weeks (P < 0.001). Iron supplementation in these animals was associated with increased lobular necroinflammation at 4 weeks (P < 0.02) and decreased hepatic steatosis (P < 0.01), hepatic triglyceride levels (P < 0.01), hepatic-conjugated dienes (CD; P < 0.02) and serum ALT levels (P < 0.002) at 12 weeks. Reduced hepatic steatosis (P < 0.005) and CD (P < 0.01) were apparent by 4 weeks. Iron supplementation was associated with a trend towards increased perivenular fibrosis not hepatic HYP content. CONCLUSION: Hepatic iron overload in the MCD model of NAFLD is associated with decreased hepatic lipid, decreased early lipid peroxidation products, increased necroinflammation and a trend towards increased perivenular fibrosis.

Alanine Transaminase↗