Carnitine-14C metabolism in choline-deficient, alloxan-diabetic choline-deficient and insulin-treated rats.
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Animals↗
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Differential regulation of liver P-450III cytochromes in choline-deficient rats: implications for the erythromycin breath test as a parameter of liver function.
Progressive liver fibrosis in rats develops when they are fed a diet deficient in choline. This diet also results in a pronounced and selective decrease in the liver microsomal content of a phase I drug-metabolizing enzyme belonging to the cytochrome P-450III gene family. Because P-450III cytochromes characteristically catalyze the N-demethylation of erythromycin, we believed that the production of breath CO2 from erythromycin would be dramatically reduced in choline-deficient rats. However, when 12 choline-deficient rats were compared with 9 control rats, the reduction in CO2 production from erythromycin (mean decrease 71%) was essentially identical to that from aminopyrine (mean decrease 69%), a substrate believed to be metabolized normally by the hepatocyte in fibrotic liver disease. Furthermore, we found that the relative erythromycin and aminopyrine demethylase activities were comparable when measured in vitro in liver microsomes prepared from the choline-deficient rats. To determine the molecular basis for the erythromycin demethylase activity in the choline-deficient rats, the liver microsomes were subjected to immunoblot analysis using a variety of polyclonal and monoclonal antibodies capable of distinguishing individual P-450III-related proteins. Our studies confirm that a major erythromycin demethylase belonging to the P-450III family, termed P-450p, was greatly reduced in the choline-deficient rat liver. However, the specific concentration of a second P-450p-related protein was essentially normal and that of a third P-450p-related protein was actually increased in the choline-deficient rat liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminopyrine↗
Are patients with cirrhosis choline deficient?
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Choline Deficiency↗
Synthesis of phosphatidylcholine by rat lung during choline deficiency.
The effect of choline deficiency on the de novo pathway for phosphatidylcholine (PC) synthesis in the lung was investigated in rats fed a washed soy protein (lipotrophic) diet deficient in choline and methionine for 2-3 wk. Lungs from lipotrophic rats showed a decreased content of choline and choline-phosphate (P less than 0.05) compared with control but no change in content of cytidine 5'-diphosphocholine or PC. Isolated perfused lungs from lipotrophic rats were evaluated for choline and fatty acid utilization for PC synthesis. Lipotrophic lungs perfused with 5 microM [14C-methyl]-choline chloride showed increased incorporation into PC while there was no significant effect at saturating levels of choline (100 microM). There was increased incorporation of [1-14C]-palmitic acid into PC and diglyceride and increased incorporation of D-[U-14C]glucose into fatty acids of PC. Increased choline and glucose incorporation was not due to alteration of intracellular specific activity of these substrates. This study indicates the utilization of choline and fatty acid for PC synthesis is stimulated as a result of choline deficiency while lung CDP-choline concentration is maintained, possibly through regulation of choline phosphate cytidyl transferase activity. These mechanisms compensate for decreased choline availability to maintain the PC content of lungs.
Animals↗
Choline-deficient diet increases Z protein concentration in rat liver.
Feeding rats a diet deficient in choline results in fatty liver within 1 d. We studied the effect of short-term (1-3 d) choline deficiency on rat liver Z protein (fatty acid-binding protein). Groups of three females Sprague-Dawley rats were fed ad libitum a purified diet lacking choline and L-methionine or were supplemented with 0.2% choline chloride and 0.82% L-methionine. Animals were killed after 1, 2 or 3 d of consuming control or experimental diets and hepatic Z protein was prepared. Z protein in livers from experimental and control rats were estimated with the fluorescent probe dansylamino undecanoic acid. The corresponding fatty acid-binding activity was also determined. One day of choline-deficient diet increased Z protein concentration threefold, reaching a plateau on the second and third day. Fatty acid-binding activity of Z protein remained unchanged.
Animals↗
Metabolism of sorbitol modified by ethanol in rats fed with a choline-deficient or choline-supplemented low-protein high-fat diet.
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Animals↗
Cirrhosis of choline deficiency in the Rhesus Monkey. Possible role of dietary cholesterol (38541).
One of five rhesus monkeys fed a diet deficient in choline and protein for 31 mo developed signs of cirrhosis at 26 mo. Five other monkeys were fed the same diet for 14 mo, at which time cholesterol comprising 2% of the diet was added. Three followed a sharp rise in hepatic lipids. One monkey developed marked hypercholesterolemia and showed signs of cirrhosis 2 mo after cholesterol supplementation. The findings indicate that the rhesus monkey is susceptible to choline-deficiency cirrhosis. They suggest that cholestrol supplementation accelerates this process.
Animals↗
Differential response of lung and liver of juvenile rats to choline deficiency.
The effect of choline deficiency on the lung lipids of actively growing male Sprague-Dawley rats was investigated using a washed soy protein diet deficient in choline and methionine (lipotrophic). The livers from deficient animals had a significantly increased total lipid content and decreased phosphatidylcholine (PC) content and PC-to-phosphatidylethanolamine ratio (P less than 0.01). Although lung free choline levels were decreased 40% compared with controls (P less than 0.05), the PC content of the whole lung homogenate was unchanged. However, disaturated phosphatidylcholine from animals receiving the lipotrophic diet was significantly increased in the lavage and proportionally decreased in the lavaged lung tissue compared with controls (P less than 0.01). This study indicates that, despite decreased lung choline levels as a result of ingesting a lipotrophic diet, and unlike the liver, lung PC content is maintained at normal values. Although the lung total PC levels are maintained, there is a change in the partition of this lipid pool between the tissue and the alveolar space.
Animals↗
Effect of low methionine, choline deficient diets upon major unsaturated phosphatidyl choline fractions of rat liver and plasma.
To see how the metabolism of specific phosphatidyl choline fractions might be affected when only a limited source of methyl groups was available, rats were fed for 7 days a low methionine, choline-deficient diet or one supplemented with either choline or methionine. Prior to killing, they were injected with -14C-methyl methionine and liver and plasma phosphatidyl choline isolated and separated by argentation chromatography into 3 major unsaturated fractions. Fatty acid composition and radioactivity of the fractions were determined. Deficient rats had reduced total liver phosphatidyl choline when compared with the supplemented groups, but the proportions of 20:4 and 22:6 fatty acids in the total phosphatidyl choline were unchanged. Plasma phosphatidyl choline also was reduced sharply by the deficiency, as was its proportion of 20:4 fatty acid. Specific activities of the liver 22:6, 20:4, and 18:2 phosphatidyl choline fractions showed that deficient rats had less radioactivity in their 20:4 and 18:2 phosphatidyl choline than did the supplemented animals. Plasma phosphatidyl choline fractions presented a similar pattern. Feeding methionine or choline nearly doubled radioactive methyl group incorporation into the 20:4 phosphatidyl choline fraction of liver and plasma, while incorporation into the 22:6 phosphatidyl choline was reduced or unchanged. The results suggested that, in the rat, limited availability of methyl groups altered the metabolism of liver and plasma phosphatidyl choline fractions. Methionine, as a source of labile methyl groups, appears necessary for the normal synthesis of certain unsaturated phosphatidyl choline fractions (particularly 20:4 phosphatidyl choline). Transmethylation of phosphatidyl ethanolamine molecular species to the corresponding phosphatidyl choline species may be an important reaction in normal lipid metabolism and transport. Relative affinities for incorporation of the labeled methyl groups into the phosphatidyl choline fractions of either deficient or supplemented rats were: 22:6 less than 20:4 less than 18:2.
Animals↗
Effect of isoprenaline on salivary gland lipids of rats fed a choline-deficient diet.
Male adult rats were fed choline deficient and a choline-supplemented diet for 3 weeks. Half the rats from each group were injected with isoprenaline (16 mg/kg body weight) and the remainder with saline. After 2 and 8 hours, rats were sacrificed, their submandibular salivary glands were disected out, and extracted for lipids. The fatty acid composition of total lipids and some neutral and phospholipid fractions were determined. Isoprenaline administration resulted in a slightly higher level of oleic acid in SMSG of rats fed choline-deficient but not the control diet. There was an increase in the free fatty acid (FFA) concentrations of the gland after 2 hours of isoprenaline treatment in rats fed the control diet; no such increase was observed in the choline-deficient group. The fatty acid composition of FFA fraction was also slightly changed as a result of isoprenaline treatment, but only in the choline-deficient group. The fatty acid composition of triglyceride (TG), phosphatidyl choline (PC), and phosphatidyl ethanolamine (PE) fractions was not changed.
Animals↗
Choline deficiency and synthesis of choline from precursors in mature Japanese quail.
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Age Factors↗
The relationship of choline and carnitine in the choline deficient rat.
Levels of carnitine in choline deficient and choline supplemented rats were measured in heart, skeletal muscle, plasma, and liver after various treatments. A decreased hepatic concentration of carnitine was shown to be closely correlated to the deficiency in dietary choline. No change in the concentration of plasma ketone bodies after a 48 hour fast was observed in the choline deficient rats when compared to choline supplemented controls, even though the level of hepatic carnitine subsequent to the fast was lower in the deficient rats. The concentration of hepatic carnitine was increased to normal values 1.5 hours after a single injection of 100 mumoles of choline, but was not affected by other "methyl" donors. From experiments presented in this communication it is concluded that the increase in hepatic carnitine is probably due to increased transport and uptake of this compound into the liver rather than by "de novo" synthesis.
Animals↗
Effect of choline deficiency on utilization of labeled precursors of choline and turnover of choline in the liver of mature Japanese quail.
Studies were conducted to determine the effect of choline deficiency on utilization of various labeled precursors of choline and rate of choline biosynthesis in mature Japanese quail. A deficiency of dietary choline did not change the in vivo incorporation of 14C-label from (1,2-14C) ETHANOLAMINE, N, N-dimethyl (1,2-14C) ethanolamine, and L-(methyl-14C) methionine into liver phosphatidylcholine (PC) or total phospholipids. Incorporation of radioactivity from (14C) serine into liver PC was increased, but the difference was not significant (PGREATER THAN3.35). In vitro studies confirmed these observations as there were no differences in liver microsomal methyltransferase activities, expressed as the incorporation of methyl-14C from labeled S-adenosylmethionine into microsomal PC from quail fed a purified diet with with or without choline. Rats appeared to incorporate an increased amount of 14C into PC when fed a diet devoid of choline, but the differences were not significant. There were differences in methyltransferase activities among species, and quail had the lowest activity. A slower turnover of choline was found in quail liver (t1/2=7.5 hours) as compared with that of hen liver (t1/2=2.0 hours). The methyltransferase responsible for the first methylation of phosphatidyl-ethanolamine from quail liver appears to differ from most other biosynthetic enzymes in that it occurs in liver and catalyzes the reaction at a slow rate but cannot adapt to exogenous choline supply to meet the requirements for normal bodily functions in quail.
Animal Nutritional Physiological Phenomena↗
Vitamin B12 improves cognitive disturbance in rodents fed a choline-deficient diet.
The effect of vitamin B12 on learning disturbance was tested in rats. Rats were fed a choline-enriched, choline-deficient, and choline-deficient diet with vitamin B12. Concentrations of acetylcholine in the brain were significantly lower in rats fed a choline-deficient diet than rats fed a choline-enriched diet. Passive avoidance learning shows that rats on a choline-deficient diet showed significantly impaired learning compared to rats on a choline-enriched diet. However, there was no significant difference of acetylcholine in the brain or in the passive avoidance learning between rats fed a choline-enriched and a choline-deficient with vitamin B12 diet. We, therefore, suggest that vitamin B12 potentiates learning in an acetylcholine-deprived brain.
Acetylcholine↗
[Influence of riboflavin on xanthuria leveloping as a result of protein and choline deficiency].
In growing male-rats intensively excreting xanthuric acid under the effect of rations deficient in protein and choline the passage of riboflavin with urine was determined. A series of tests with deficient choline in conjunction with a well-marked protein shortage revealed an intensive passage of riboflavin. On the other hand, a series of tests with deficient choline against the background of a moderate protein shortage failed to show any difference in the passage of riboflavin by test and control anomals. A single administration of 200 gamma of riboflavin to rats helped bring down elevated concentrations of xanthuric acid in the urine.
Animals↗
Ethanol lowers heart carnitine in the methionine and choline deficient rat.
In agreement with the findings of others, heart carnitine levels of male, weanling Sprague-Dawley rats fed nutritionally adequate liquid diets with 35% of calories as ethanol for 3 weeks were not different from control or pair-fed rats (Experiment 1). When ethanol was given as 30% of energy in combination with a diet deficient in methionine and choline, and the feeding period was extended to 5 weeks, heart carnitine levels were significantly affected (Experiment 2). Carnitine levels in whole heart homogenates of the methionine and choline deficient chronic ethanol-fed group were 2.14 +/- 0.74 mumoles per g dry wt. significantly lower (p less than 0.05) than deficient controls, 3.08 +/- 0.85 mumoles per g dry wt. We conclude that a methionine and choline deficient diet exacerbates the effects of alcohol on methyl-group metabolism so as to produce decrements in heart carnitine not seen when alcohol is given with an adequate diet.
Alcoholism↗
Choline deficiency causes translocation of CTP:phosphocholine cytidylyltransferase from cytosol to endoplasmic reticulum in rat liver.
The choline-deficient rat liver has been chosen as a physiologically relevant model system in which to study the regulation of phosphatidylcholine biosynthesis. When 50-g rats were placed on a choline-deficient diet for 3 days, the activity of CTP:phosphocholine cytidylyltransferase (CT) was increased 2-fold in the microsomes and decreased proportionately in the cytosol. A low titer antibody to CT was obtained from chickens and used to identify the amount of CT protein in cytosol from rat liver. The amount of CT recovered from the choline-deficient cytosol was significantly less than in cytosol from choline-supplemented rats. When hepatocytes were prepared from choline-deficient livers, supplementation of the medium of the cells with choline caused CT to move from the membranes to cytosol within 1-2 h. The activity of another translocatable enzyme of glycerolipid metabolism, phosphatidate phosphohydrolase, was unchanged in cytosol from choline-deficient rat livers, and the microsomal activity of this enzyme was only minimally increased. When the livers were fractionated into endoplasmic reticulum and Golgi, there was a 2-fold increase in the activity on the endoplasmic reticulum from choline-deficient livers but no change in activity associated with Golgi. Thus, the increased association of CT with endoplasmic reticulum in choline-deficient livers appears to be specific to that subcellular fraction, and the subcellular location of other enzymes may not be affected.
Animals↗
Aflatoxin-DNA adduct formation in chronically dosed rats fed a choline-deficient diet.
Nutritional modulation of male Fischer rats by a choline-deficient/methionine-low diet dramatically increases hepatocarcinogenesis and reduces time to first tumors induced by aflatoxin B1 (AFB1). The effect of this diet on hepatic aflatoxin-DNA adduct burden in male Fischer rats dosed with a carcinogenic regimen of AFB1 was examined in this study. After 3 weeks of ingestion of a choline-deficient/methionine-low diet or control semi-purified diet, rats were administered a carcinogenic regimen of 25 micrograms [3H]AFB1 for 5 days a week over 2 weeks. Six choline-deficient and four control diet rats were killed 2 h after each dose, and liver DNA isolated. In addition, hepatic DNA was isolated from animals 1, 2, 3, and 11 days after the last [3H]AFB1 administration. At all time points HPLC analysis of aflatoxin-DNA adducts was performed to confirm radiometric determinations of DNA binding levels. No significant quantitative differences in AFB1-DNA adduct formation between the dietary groups were observed following the first exposure to [3H]AFB1; however, total aflatoxin-DNA adduct levels in the choline-deficient animals were significantly increased during the multiple dose schedule. When total aflatoxin-DNA adduct levels were integrated over the 10 day dose period, a 41% increase in adduct burden was determined for the choline-deficient animals. While this increase in DNA damage is consistent with the hypothesis that DNA damage is related to tumor outcome, the biochemical basis for this effect still needs to be elucidated.
Aflatoxin B1↗