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↗
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Hepatic liposis and myocardial damage in mice fed choline-deficient or choline-supplemented diets.
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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↗
Effects of choline deficiency and methotrexate treatment upon rat liver.
Choline deficiency and treatment with methotrexate (MTX) both are associated with fatty infiltration of the liver. Choline, methionine, and folate metabolism are interrelated and converge at the regeneration of methionine from homocysteine. MTX perturbs folate metabolism, and it is possible that it also influences choline metabolism. We fed rats a choline deficient diet for 2 weeks and/or treated them with methotrexate (MTX; 0.1 mg/kg daily). Choline deficiency lowered hepatic concentrations of choline (to 43% control), phosphocholine (PCho; to 18% control), glycerophosphocholine (GroPCho; to 46% control), betaine (to 30% control), phosphatidylcholine (PtdCho; to 62% control), methionine (to 80% control), and S-adenosylmethionine (AdoMet; to 57% control), while S-adenosylhomocysteine (AdoHcy) and triacylglycerol concentrations increased (to 126% and 319% control, respectively). MTX treatment alone lowered hepatic concentrations of PCho (to 48% control), GroPCho (to 69% control), betaine (to 55% control), and AdoMet (to 75% control). The addition of MTX treatment to choline deficiency resulted in a larger decrease in AdoMet concentrations (to 75% control) and larger increases in AdoHcy and triacylglycerol concentrations (to 150% and 500% control, respectively) than was observed in choline deficiency alone. Livers from MTX-treated animals used radiolabeled choline to make the same metabolites as did livers from controls (most of the label was converted to PCho and betaine). In choline deficient animals, most of the labeled choline was converted to PtdCho. Therefore, MTX depleted hepatic PCho, GroPCho, and betaine by a mechanism that was different from that of choline deficiency. MTX increased the extent of fatty infiltration of the liver in choline deficient rats, and choline deficiency and MTX treatment damaged hepatocytes as measured by leakage of alanine aminotransferase activity. Our data are consistent with the hypothesis that the fatty infiltration of the liver associated with MTX treatment occurs because of a disturbance in choline metabolism.
Journal Article↗
Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts.
BACKGROUND: Choline is a required nutrient, and humans deprived of choline develop liver damage. OBJECTIVE: This study examined the effect of choline deficiency on muscle cells and the release of creatine phosphokinase (CPK) as a sequela of that deficiency. DESIGN: Four men were fed diets containing adequate and deficient amounts of choline, and serum was collected at intervals for measurement of CPK. C2C12 mouse myoblasts were cultured in a defined medium containing 0 or 70 micromol choline/L for up to 96 h, and CPK was measured in the media; choline and metabolites were measured in cells. Apoptosis was assessed by using terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling and activated caspase-3 immunohistochemistry. Cell fragility in response to hypo-osmotic stress was also assessed. RESULTS: Three of 4 humans fed a choline-deficient diet had significantly elevated serum CPK activity derived from skeletal muscle (up to 66-fold; P < 0.01) that resolved when choline was restored to their diets. Cells grown in choline-deficient medium for 72 h leaked 3.5-fold more CPK than did cells grown in medium with 70 micromol choline/L (control medium; P < 0.01). Apoptosis was induced in cells grown in choline-deficient medium. Phosphatidylcholine concentrations were diminished in choline-deficient cells (to 43% of concentrations in control cells at 72 h; P < 0.01), as were concentrations of intracellular choline, phosphocholine, and glycerophosphocholine. Cells grown in choline-deficient medium had greater membrane osmotic fragility than did cells grown in control medium. CONCLUSIONS: Choline deficiency results in diminished concentrations of membrane phosphatidylcholine in myocytes, which makes them more fragile and results in increased leakage of CPK from cells. Serum CPK may be a useful clinical marker for choline deficiency in humans.
Adult↗
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↗
Diurnal changes in liver and plasma lipids of choline-deficient rats.
Early effects of choline deficiency were studied in rats. Nonphospholipid ("neutral lipid") and phospholipid were measured in plasma and in three fractions of a liver homogenate: sediment, supernatant fraction, and "floating fat." A single choline-deficient meal caused significant aberrations from the typical diurnal changes observed in the lipid fractions of the controls. These changes occurred in the following sequence: (a) failure of phospholipid to increase, after feeding, in the sediment fraction; (b) increase of neutral lipid, compared with controls, exclusively in the floating fraction; and (c) failure of neutral lipid to return to control levels. The rate of accumulation of neutral lipid increased during the first 4 days of deficiency. The occurrence of NADH-cytochrome c dehydrogenase in the floating fat and the absence of succinate dehydrogenase activity point to microsomal origin of the floating fat. Early effects of choline deficiency on plasma lipids were limited to phospholipid, and occurred later than changes in the liver. Plasma nonphospholipid levels were unchanged during the first 2 days; this does not support impaired secretion or transportation of glyceride as the cause of fatty liver in the early stages of choline deficiency.
Animals↗
Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet.
Mice that lack phosphatidylethanolamine-N-methyltransferase (PEMT) and are fed a choline-deficient (CD) diet suffer severe liver damage and do not survive. Since phosphatidyldimethylethanolamine (PDME) has physical properties similar to those of phosphatidylcholine (PC), we hypothesized that dimethylethanolamine (DME) would be converted into PDME that might substitute for PC, and therefore abrogate the liver damage in the Pemt -/- mice fed a CD diet. We fed Pemt -/- mice either a CD diet, a CD diet supplemented with choline, or a CD diet supplemented with DME (CD + DME). Pemt -/- mice fed the CD diet developed severe liver failure by 4 days while CD + DME-fed mice developed severe liver failure by 5 days. The hepatic PC level in choline-supplemented (CS) mice was 67 +/- 4 nmol/mg protein, whereas the PC content was reduced in CD- and CD + DME-fed mice (49 +/- 3 and 30 +/- 3 nmol/mg protein, respectively). Upon supplementation of the CD diet with DME the amount of hepatic PDME was 81 +/- 9 nmol/mg protein so that the hepatic content of PC + PDME combined was 111 nmol/mg protein. Moreover, plasma apolipoprotein B100 and Al levels were markedly lower in mice fed the CD + DME diet compared to mice fed the CS diet, as was the plasma content of PC. Thus, despite replacement of the deficit in hepatic PC with PDME in Pemt -/- mice fed a CD diet, normal liver function was not restored. We conclude that although PC and PDME exhibit similar physical properties, the three methyl groups of choline are required for hepatic function in mice.
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↗
Peripheral airway hyperresponsiveness in the choline-deficiently fed rat.
Rats fed with choline-deficient diets are known as a model of aging and learning impairments due to acetylcholine (ACh) deficiency in the brain which may be associated with a decrease in acetylcholinesterase (AChE; EC 3.1.1.7). To determine the role of AChE in bronchial responsiveness, we examined the contractile response of isolated lung parenchymal strips to ACh in control rats and rats fed with choline-deficient diets. Concentration-response curves to ACh shifted to the lower concentrations and the maximum response to ACh was greater in rats fed with choline-deficient diets than in control rats (P < 0.01). Physostigmine (10(-6) M) mimicked effects of choline-deficient diets on the contractile response to ACh. However, concentration response curves to carbachol and 5-hydroxytryptamine did not differ between control rats and rats fed with choline-deficient diets. Choline-deficient diets significantly decreased the AChE activity from homogenates of lung parenchymal tissues (P < 0.01). These results suggest that a decrease in AChE activity of lung tissues may relate to airway hyperresponsiveness to ACh.
Acetylcholine↗
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↗
Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.
BACKGROUND: Whereas deficiency of the essential nutrient choline is associated with DNA damage and apoptosis in cell and rodent models, it has not been shown in humans. OBJECTIVE: The objective was to ascertain whether lymphocytes from choline-deficient humans had greater DNA damage and apoptosis than did those from choline-sufficient humans. DESIGN: Fifty-one men and women aged 18-70 y were fed a diet containing the recommended adequate intake of choline (control) for 10 d. They then were fed a choline-deficient diet for up to 42 d before repletion with 138-550 mg choline/d. Blood was collected at the end of each phase, and peripheral lymphocytes were isolated. DNA damage and apoptosis were then assessed by activation of caspase-3, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and single-cell gel electrophoresis (COMET) assays. RESULTS: All subjects fed the choline-deficient diet had lymphocyte DNA damage, as assessed by COMET assay, twice that found when they were fed the control diet. The subjects who developed organ dysfunction (liver or muscle) when fed the choline-deficient diet had significantly more apoptotic lymphocytes, as assessed by the activated caspase-3 assay, than when fed the control diet. CONCLUSIONS: A choline-deficient diet increased DNA damage in humans. Subjects in whom these diets induced liver or muscle dysfunction also had higher rates of apoptosis in their peripheral lymphocytes than did subjects who did not develop organ dysfunction. Assessment of DNA damage and apoptosis in lymphocytes appears to be a clinically useful measure in humans (such as those receiving parenteral nutrition) in whom choline deficiency is suspected.
Adolescent↗
Restricting food intake does not exacerbate the effects of a choline-deficient diet on tissue carnitine concentrations in rats.
Previous reports in animals indicate that choline deficiency alters carnitine metabolism. Recent studies in humans suggest that choline deficiency occurs in individuals during long term total parenteral nutrition. Malnutrition is also a frequent complication in this population. We therefore examined the effect of restricting the intake of a choline-deficient diet on carnitine concentrations in plasma and tissues. Adult male rats were randomly assigned to one of four dietary regimens: control, choline deficient, restricted control (85% of control), or restricted choline deficient for 42-43 d. At the end of the experimental period, restricted animals weighed significantly less than their respective controls (P < 0.01). Liver weight relative to body weight and fat concentration were greater in choline-deficient animals (P < 0.01 and 0.001, respectively). Choline-deficient rats fed free access had elevated plasma carnitine concentration (P < 0.01). Urinary carnitine excretion was elevated in both groups of choline-deficient rats (P < 0.01), while liver, heart and muscle carnitine concentrations were lower than in controls (P < 0.05). Restricting dietary intake reduced plasma carnitine concentration in choline-deficient animals (P < 0.01), but did not alter tissue or urine carnitine concentrations in either group. Restricted, choline-deficient animals did not exhibit a worsening of the sequelae of choline deficiency. We conclude that choline deficiency alters carnitine concentrations in plasma and tissues and that restricting the intake of a choline-deficient diet does not alter this effect in tissues.
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↗
Hepatic free choline and betaine and the utilization of dietary protein in the choline-deficient rat.
In the rat, exclusion of choline from a carbohydrate-rich, 10% casein diet, resulted in a drastic reduction of betaine in the liver. The amount of unesterified choline was not lowered to the same extent. Both unesterified choline and total lipids in the liver were increased by rats fed a choline-deficient diet supplemented with 0.5% L-methionine compared to rats given an unsupplemented choline-deficient diet. The amount of betaine was low in both groups compared to choline-supplemented rats. Dietary choline deficiency lowered the biological value of casein only slightly. Statistically significant effects were seen only in some of the experiments when potato starch was used as the carbohydrate source but not when maize starch was used. The choline-deficient potato starch diet gave rise to a more severe liver fattening that the corresponding maize starch diet.
Adipose Tissue↗
Ocular lesions and experimental choline deficiency.
Previous studies have shown ocular haemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline-deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one of them were fed a choline-deficient diet and the rest was fed a choline-supplemented diet ad libitum. Animals from both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution light microscopy and the study of the retina as "rétine a plat". Kidneys were studied by light microscopy. Choline-supplemented rats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only choline-deficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras and ciliary and vitreous bodies. Correlations between ocular and renal lesion (r = 0.72, p < 0.0001, CI 95%: 0.48-0.86); ocular lesion and creatinine (r = 0.86, p < 0.0001, Cl 95%: 0.72-0.93) and ocular lesion and urea (r = 0.70, p < 0.0001, Cl 95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved.
Analysis of Variance↗