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PubMed2007

Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy.

OBJECTIVE: The aim of this study was to assess the influence of severe steatosis with inflammation on hepatocellular recovery after 70% hepatectomy in a rat model of diet-induced steatosis. BACKGROUND: Patients with steatosis have an increased risk of inflammatory complications after liver resection. This might be attributable to Kupffer cell-mediated inflammation in steatotic livers causing progressive injury. METHODS: Male Wistar rats were fed a standard methionine- and choline-deficient diet for 1 or 5 weeks. A 70% partial hepatectomy (PH) was performed, after which rats were killed at 24, 48, or 72 hours. The extent of steatosis and inflammation was determined by assessment of hepatic triglycerides, cytokine content, and histopathology. Outcome parameters were: liver regeneration (MIB-5 proliferation rate, mitotic index, and regenerating liver mass), hepatocellular injury (plasma aminotransferases, lipid peroxidation, histopathology, and apoptosis), Kupffer cell-mediated proinflammatory response (TNF-alpha, IL-1beta, IL-6, IL-10 in plasma and liver) and antioxidant content (total glutathione). RESULTS: Methionine- and choline-deficient diet induced uncomplicated steatosis after 1 week (<30% hepatocytes affected without inflammation) and severe steatosis after 5 weeks (>60% hepatocytes affected, including prominent inflammation) as confirmed by histopathology. After PH, liver regeneration was impaired at all time points in the severe steatosis group as compared with the mild and control groups (P < 0.05). Hepatocellular injury was significantly increased in the severe steatosis group at all time points (P < 0.05). Kupffer cell-mediated inflammatory responses were aggravated in the severe steatosis group along with decreased antioxidant content (P < 0.05). Necrosis was the main type of cell death in severe steatotic livers compared with mainly apoptotic cell death in mild steatotic and normal livers. CONCLUSION: Steatosis with prominent inflammation impaired liver regeneration probably because of increased hepatocellular lipid peroxidation and damage in concert with Kupffer cell-mediated proinflammatory responses. These results suggest an increased risk of performing extensive liver resection in the presence of severe steatosis.

Animals↗
PubMed2006

Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats.

AIM: Peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been shown to prevent hepatic fibrosis in rodents. We evaluated the therapeutic antifibrotic potential of the PPARgamma agonist pioglitazone on established hepatic fibrosis. METHODS: Repeated injections of carbon tetrachloride (CCl4), a choline deficient diet, or bile duct ligation (BDL) were used to induce hepatic fibrosis in rats. Pioglitazone treatment was introduced at various time points. Therapeutic efficacy was assessed by comparison of the severity of hepatic fibrosis in pioglitazone treated versus untreated fibrotic controls. RESULTS: When introduced after two weeks of CCl4, pioglitazone reduced hepatic fibrosis, OH proline content, hepatic mRNA expression of collagen type I, and profibrotic genes, as well as the number of activated alpha smooth muscle actin positive hepatic stellate cells, compared with rats receiving CCl4 only, with no significant change in necroinflammation. When pioglitazone treatment was initiated after five weeks of CCl4, no antifibrotic effect was observed. Similarly, pioglitazone was associated with a reduced severity of fibrosis induced by a choline deficient diet when introduced early, while delayed treatment with pioglitazone remained ineffective. In contrast, pioglitazone failed to interrupt progression of fibrosis due to BDL, irrespective of the timing of its administration. CONCLUSION: In rats, the therapeutic antifibrotic efficacy of pioglitazone is limited and dependent on the type of injury, duration of disease, and/or the severity of fibrosis at the time of initiation of treatment.

Animals↗
PubMed2004

Deletion of the Pemt gene increases progenitor cell mitosis, DNA and protein methylation and decreases calretinin expression in embryonic day 17 mouse hippocampus.

Choline is a required nutrient and is derived from the diet as well as from de novo synthesis catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). We previously reported that choline availability during pregnancy alters mitosis and neuronal protein expression during fetal brain development in wild-type mice and rats, and that Pemt-/- mice become choline deficient. In this study, we examined brain development in these knockout mice. Pregnant Pemt-/- and wild-type mice were fed AIN-76A diet until gestation day 17 (E17) when the fetal brains were harvested. Phosphorylation of histone H3 (a measure of mitosis) and calretinin (a GABAergic neuronal marker) were assessed in hippocampal regions. We observed increased numbers of phosphorylated histone H3 positive cells in the Pemt-/- mice (up 54% compared to wild-type mice; p<0.01). We also found decreased calretinin labeling in Pemt-/- (down to 43% compared to wild-type mice; p<0.01). Thus, there was increased stem cell proliferation in the neuroepithelium and decreased GABAergic neuronal differentiation of these animals on E17. These results are opposite to what would have been expected in choline-deficient mice. The concentrations of S-adenosylmethionine (up 21%; p<0.05) and methylation of DNA (up 46%) and proteins (up 12%; p<0.01) in hippocampus were significantly increased in Pemt-/- mice, suggesting that increased S-adenosylmethionine availability may mediate the observed developmental changes. This is the first report of altered brain development in Pemt-/- mice.

Acyltransferases↗
PubMed2004

Assessment of donor liver steatosis: pathologist or automated software?

Steatosis in donor liver biopsy specimens has been shown to correlate with graft dysfunction after orthotopic liver transplantation. This 2-part (laboratory pilot, clinical retrospective) study compared the traditional interpretation of steatosis by a pathologist with an automated measurement determined by an image analysis system. In our pilot study, Sprague-Dawley rats were studied prospectively by feeding them a choline-deficient diet for up to 7 days. In our clinical group, data from 49 consecutive recipients of cadaveric liver transplantation were reviewed retrospectively. In both studies, the percentages of microvesicular fat, macrovesicular fat, and total fat content within liver biopsy specimens were determined by an automated image analysis software program and a pathologist using the same set of slides. The association between fat content of the donor liver and patient survival and graft survival, along with levels of aspartate aminotransferase, alanine aminotransferase, prothrombin time, and total bilirubin after transplantation, were also examined in the clinical study. A direct correlation was observed between levels of macrovesicular fat determined by a pathologist and the automated software using livers from rats fed a choline-deficient diet and livers from deceased donors. A significant association was observed between macrovesicular fat content in the donor liver biopsy and graft survival by both techniques. We conclude that an image analysis system can be used to automate the determination of fat content in liver biopsy specimens, and that its findings correlate with both the visual interpretation by a pathologist and graft survival. Further study is needed to determine the role of an automated technique in the evaluation of donor livers for transplantation.

Animals↗
PubMed1994

Drug-metabolizing enzyme activities in freshly isolated oval cells and in an established oval cell line from carcinogen-fed rats.

The activities of several different phase I and phase II drug-metabolizing enzymes were measured in freshly isolated oval cells from rats fed a choline-deficient/DL-ethionine-supplemented diet for 6 weeks and also in vitro in the established oval cell line OC/CDE 6. No cytochrome P450 was spectrophotometrically measurable in both preparations and two cytochrome P450-dependent monoxygenase activities, aminopyrine N-demethylase and ethoxyresorufin O-deethylase, could not be detected in the oval cells of both sources. However, cytosolic glutathione transferase, microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities were clearly measurable in oval cells. Similar enzyme activities were found in freshly isolated and cultured oval cells. The highest activities of these three enzymes were detected during the exponential growth phase of the cultured cells; thereafter the activities decreased until the cells reached confluency. Changes in phenol UDP-glucuronosyltransferase (UGT1A1) mRNA levels paralleled the variations in UDP-glucuronosyltransferase activity, i.e. they were high in exponentially growing oval cells and low in confluent cell cultures. Taking into account that oval cells are able to proliferate in the livers of rats continuously fed a choline-deficient/DL-ethionine-supplemented diet and that none of the analyzed drug metabolizing enzymes are involved in the activation or detoxication of DL-ethionine, the described pattern might be part of a more general, nonspecific, protection mechanism enabling these cells to overcome the cytotoxic effects of a variety of carcinogens and to proliferate even in their presence. Furthermore, the expression of microsomal epoxide hydrolase, cytosolic glutathione transferase and UDP-glucuronosyltransferase appears to depend on the proliferative status of the cells.

Animals↗
PubMed1995

Lectin histochemistry of lipofuscin and certain ceroid pigments.

Little is known at present about the saccharide components of lipofuscin (age pigment) and ceroid pigments in situ. The purpose of this study was, therefore, to study in detail the lectin reactivities of lipofuscin in neurons and cardiac myocytes of old humans and rats. In addition, those of diverse ceroid pigments found in human aortic atheromas, in the livers of choline-deficient rats, in the uteri of vitamin E-deficient rats and in the crushed epididymal fat pad of rats, are included. Cryostat and deparaffinized sections from all these tissues were either extracted with a solvent mixture of chloroform-methanol-water (10:10:3, v/v) and incubated with 7 different biotinylated lectins or left untreated. Delipidation was done in order to study whether it was possible to discriminate between the saccharide moieties of glycolipids and glycoproteins of lipofuscin and ceroid pigments in situ. Other similarly treated sections were used to study the autofluorescence, sudanophilia, acid-fastness and reactivity to PAS. The frequency and intensity of lectin binding and standard histochemical properties of all the pigments were evaluated semi-quantitatively and blind. The results indicated that mannose was in general the most consistently detected sugar residue in lipofuscin granules of humans and rats, and that this pigment may also contain acetylglucosamine, acetylgalactosamine, sialic acid, galactose and fucose. However, notable differences were found not only in the lipofuscin saccharide components of different cell types of humans and rats, but also in those in the same type of cells in both species. Although mannose was not detected in the hepatic ceroid of choline-deficient rats, this saccharide moiety was almost always present in the other ceroid pigments. Each of the ceroids also contained other types of saccharides although the frequency of the latter varied between different ceroid pigments. While lipofuscin and each of the ceroid pigments showed somewhat different lectin binding patterns, the variability in the frequency of reactivity to lectins suggests that these patterns may not be permanent but transient. In this sense, it appears that lectin histochemistry may not allow these pigments to be differentiated. Furthermore, the extractive procedures used in this study did not enable us to determine whether the saccharides detected in the pigments in situ corresponded to glycolipids or glycoproteins.

Aged↗
PubMed2006

Oral administration of S-nitroso-N-acetylcysteine prevents the onset of non alcoholic fatty liver disease in rats.

AIM: To evaluate the potential of S-nitroso-N-acetylcysteine (SNAC) in inhibition of lipid peroxidation and the effect of oral SNAC administration in the prevention of nonalcoholic fatty liver disease (NAFLD) in an animal model. METHODS: NAFLD was induced in Wistar male rats by choline-deficient diet for 4 wk. SNAC-treated animals (n=6) (1.4 mg/kg per day of SNAC, orally) were compared to 2 control groups: one (n=6) received PBS solution and the other (n=6) received NAC solution (7 mg/kg per day). Histological variables were semiquantitated with respect to macro and microvacuolar fat changes, its zonal distribution, foci of necrosis, portal and perivenular fibrosis, and inflammatory infiltrate with zonal distribution. LOOHs from samples of liver homogenates were quantified by HPLC. Nitrate levels in plasma of portal vein were assessed by chemiluminescence. Aqueous low-density lipoprotein (LDL) suspensions (200 microg protein/mL) were incubated with CuCl(2) (300 micromol/L) in the absence and presence of SNAC (300 micromol/L) for 15 h at 37 degree Celsius. Extent of LDL oxidation was assessed by fluorimetry. Linoleic acid (LA) (18.8 micromol/L) oxidation was induced by soybean lipoxygenase (SLO) (0.056 micromol/L) at 37 degree Celsius in the presence and absence of N-acetylcysteine (NAC) and SNAC (56 and 560 micromol/L) and monitored at 234 nm. RESULTS: Animals in the control group developed moderate macro and microvesicular fatty changes in periportal area. SNAC-treated animals displayed only discrete histological alterations with absence of fatty changes and did not develop liver steatosis. The absence of NAFLD in the SNAC-treated group was positively correlated with a decrease in the concentration of LOOH in liver homogenate, compared to the control group (0.7+/-0.2 nmol/mg vs 3.2+/-0.4 nmol/mg protein, respectively, P<0.05), while serum levels of aminotransferases were unaltered. The ability of SNAC in preventing lipid peroxidation was confirmed in in vitro experiments using LA and LDL as model substrates. CONCLUSION: Oral administration of SNAC prevents the onset of NAFLD in Wistar rats fed with choline-deficient diet. This effect is correlated with the ability of SNAC to block the propagation of lipid peroxidation in vitro and in vitro.

Acetylcysteine↗
PubMed1976

Evidence for a synaptically mediated decrease in conductance in a crustacean myocardium.

1. In the neurogenic heart of the isopod Porcellio dilatatus, electrical stimulation of the cardio-regulatory nerves at rates greater than 20-25 pulses/s elicited inhibitory junctional potentials (IJPs) in the myocardium. Its cessation was followed by a long lasting hyperpolarization of myocardial membrane (post-stimulus hyperpolarization = PSH). 2. During the PSH the membrane resistance of the heart muscle increased. The PSH was enhanced by myocardium hyperpolarization, decreased by depolarization and reversed around -50 mV. 3. Picrotoxin inhibited the summated IJPs elicited by the stimulation and thus caused the membrane to maximally hyperpolarize during inhibitory train, thus suggesting a composite nature of the inhibitory processes. 4. The PSH was reversibly reduced in K+-free saline or in ouabain containing saline but partial restoration was obtained by injection of inward current to the myocardium. 5. The PSH was abolished in lithium saline and reduced in Na+-deficient (choline) solution. Cl-deficient solution that markedly affected the summated IJPs shortly after its introduction did not affect the PSH. 6. It is proposed that the PSH results from a decrease in conductance, presumably to both Na+ and K+. The implication of such a mechanism as a component of the inhibitory regulation of this crustacean heart is discussed.

Animals↗
PubMed1992

Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients.

Plasma-free choline levels have previously been found below normal in patients receiving long term parenteral nutrition (TPN). In a group of 15 patients receiving home TPN who had low plasma free choline levels (6.3 +/- 0.8 mmol/L), we found 50% had hepatic steatosis. These patients were given oral lecithin or placebo in a double-blind randomized trial for 6 weeks. Lecithin supplementation led to an increase in plasma free choline of 53.4% +/- 15.4% at 2 weeks (P = 0.04), which continued at 6 weeks. The placebo group had no change in plasma-free choline at 2 weeks, but a significant decrease of 25.4% +/- 7.1% (P = 0.01) at 6 weeks. A significant and progressive decrease in hepatic fat was indicated by increased liver-spleen CT Hounsfield units at 2 and 6 weeks (7.5 +/- 1.7 units, P = 0.02; 13.8 +/- 3.5 units, P = 0.03) in the lecithin supplemental group. Nonsignificant changes were seen in the placebo group. It was concluded that hepatic steatosis in many patients receiving long term TPN is caused by plasma-free choline deficiency and may be reversed with lecithin supplementation. Choline is a conditionally essential nutrient in this population.

Aged↗
PubMed1994

Expression of L- and M2-pyruvate kinases in proliferating oval cells and cholangiocellular lesions developing in the livers of rats fed a methyl-deficient diet.

Male outbred Sprague-Dawley rats were fed a choline-deficient diet containing 0.1% w/w DL-ethionine (CDE) for up to 22 weeks. The expression of the pyruvate kinase isoenzymes L (L-PK) and M2 (M2-PK) was immunohistochemically analyzed in liver slices from rats killed 4, 10, 14 and 22 weeks after starting the treatment. M2-PK was detected in bile duct epithelial cells of untreated rats and in proliferating oval cells, cholangiofibroses and cholangiofibromas of CDE-fed animals. Thus, M2-PK can be viewed as a positive marker of the bile duct epithelial/oval cell compartment. L-PK, a parenchymal cell-specific protein in untreated rat liver, was not present in proliferating oval cells, but was consistently observed in cells that were part of the ductal structures in the cholangiofibroses and cholangiofibromas. Based on their morphology, the L-PK-positive duct cells were undoubtedly part of the bile duct epithelial cell lineage and no L-PK-positive hepatocyte-like cells were observed in the ducts. Hence, this study clearly shows that the mere presence of a liver parenchymal cell marker in cells of the bile duct epithelial/oval cell compartment does not necessarily preclude that these cells are undergoing a differentiation into preneoplastic parenchymal cells, as has previously been suggested.

Animals↗
PubMed2003

Choline availability during embryonic development alters the localization of calretinin in developing and aging mouse hippocampus.

Choline availability in the diet during pregnancy alters fetal brain biochemistry with resulting behavioral changes that persist throughout the lifetime of the offspring. In the present study, the effects of dietary choline on the onset of GABAergic neuronal differentiation in developing fetal brain, as demarcated by the expression of calcium binding protein calretinin, are described. In these studies, timed-pregnant mice were fed choline supplemented, control or choline deficient AIN-76 diet from day 12-17 of pregnancy and the brains of their fetuses were studied on day 17 of gestation. In the primordial dentate gyrus, we found that pups from choline deficient-dams had more calretinin protein (330% increase), and pups from choline supplemented-dams had less calretinin protein (70% decrease), than did pups from control-dams. Importantly, decreased calretinin protein was still detectable in hippocampus in aged, 24-month-old mice, born of choline supplemented-dams and maintained since birth on a control diet. Thus, alterations in the level of calretinin protein in fetal brain hippocampus could underlie the known, life long effects of maternal dietary choline availability on brain development and behavior.

Aging↗
PubMed1997

Diet, apoptosis, and carcinogenesis.

It is known that long-term withdrawal of choline from the diet induces hepatocellular carcinomas in animal models in the absence of known carcinogens. We hypothesize that a choline deficient diet (CD) alters the balance of cell growth and cell death in hepatocytes and thus promotes the survival of clones of cells capable of malignant transformation. When grown in CD medium (5 microM or 0 microM choline) CWSV-1 rat hepatocytes immortalized with SV40 large T-antigen underwent p53-independent apoptosis (terminal dUTP end-labeling of fragmented DNA; laddering of DNA in agarose gel). CWSV-1 cells which were adapted to survive in 5 microM choline acquired resistance to CD-induced apoptosis and were able to form hepatocellular carcinomas in nude mice. These adapted CWSV-1 cells express higher amounts of both the 32 kDa membrane-bound and 6 kDa mature form of TGF alpha compared to cells made acutely CD. Control (70 microM choline) and adapted cells, but not acutely deficient hepatocytes, could be induced to undergo apoptosis by neutralization of secreted TGF alpha. Protein tyrosine phosphorylation is known to protect against apoptosis. We found decreased EGF receptor tyrosine phosphorylation in acutely choline deficient CWSV-1 cells. TGF beta 1 is an important growth-regulator in the liver. CWSV-1 cells express TGF beta 1 receptors and this peptide induced cell detachment and death in control and acutely deficient cells. Hepatocytes adapted to survive in low choline were also resistant to TGF beta 1, although TGF beta 1 receptors and protein could be detected in the cytoplasm of these cells. The non-essential nutrient choline is important in maintaining plasma membrane structure and function, and in intracellular signaling. Our results indicate that acute withdrawal of choline induces p53-independent programmed cell death in hepatocytes, whereas cells adapted to survive in low choline are resistant to this form of apoptosis, as well as to cell death induced by TGF beta 1. Our results also suggest that CD may induce alterations (mutations?) in growth factor signaling pathways which may enhance cell survival and malignant transformation.

Animals↗
PubMed2002

Seizure-induced memory impairment is reduced by choline supplementation before or after status epilepticus.

Prenatal choline supplementation can protect rats against cognitive deficits induced by status epilepticus induced by the cholinergic agent pilocarpine [J. Neurosci. 20 (2000) 1]. In the present day, we have extended this novel finding by investigating the effects of pre- and postnatal choline supplementation in memory deficits associated with status epilepticus induced with kainic acid (KA). In the first experiment pregnant rats received a normal, choline-supplemented, or choline deficient diet starting on the 11th day of gestation and continuing until postnatal (P) 7. At P42, rats were given a convulsant dosage of KA. Two weeks following the KA-induced status epilepticus rats underwent testing of visual-spatial memory using the Morris water maze test. Rats receiving supplemental choline performed better in the water maze than the deficient and control groups. Moreover, the activity of hippocampal choline acetyltransferase was 18% lower in the choline deficient animals as compared with the other two groups. In the second experiment we administered KA to P35 rats that had been given a normal diet. Following the status epilepticus the rats were given a choline-supplemented or control diet for 4 weeks and then tested in the water maze. Rats receiving choline supplementation performed far better than rats receiving a regular diet. This study demonstrates that choline supplementation prior to or following KA-induced status epilepticus can protect rats from memory deficits induced by status epilepticus.

Animals↗
PubMed1999

The unique acyl chain specificity of biliary phosphatidylcholines in mice is independent of their biosynthetic origin in the liver.

The liver synthesizes phosphatidylcholine (PC) de novo from choline via the CDP-choline pathway, and from phosphatidylethanolamine (PE) via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway. Significant amounts of PC, which are highly specific in their acyl chain composition, are secreted into bile by the liver. To determine whether either of the 2 PC biosynthetic routes is sufficient to provide physiological PC concentrations in bile, or is responsible for the unique acyl chain composition of bile PC, we analyzed gallbladder bile composition in mice that synthesized PC either via the PEMT pathway (induced by feeding a choline-deficient diet) or the CDP-choline pathway (based on genetic PEMT-deficiency). The PC concentration in gallbladder bile of mice that synthesize PC mainly via the CDP-choline pathway was comparable with control mice that synthesize PC via both pathways, whereas it was reduced by approximately 40% in mice that synthesize PC via the PEMT pathway. The acyl chain composition of bile PC was similar irrespective of the active PC biosynthetic pathway in the liver. These data demonstrate that the CDP-choline pathway alone, but not the PEMT pathway alone, can account for physiological concentrations of PC in gallbladder bile. Moreover, the specificity of biliary PC fatty acyl composition is determined independently from the synthetic origin of PC.

Animals↗
PubMed2006

COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator.

The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator-activated receptor alpha knockout (PPAR-alpha-/-) mice were fed a lipogenic, methionine- and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR-alpha-/- mice. Induction of COX-2 was completely prevented by dietary supplementation with the potent PPAR-alpha agonist Wy-14,643 in WT but not PPAR-alpha-/- mice. COX-2 upregulation was preceded by activation of nuclear factor kappaB (NF-kappaB) and coincided with increased levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and intercellular adhesion molecule 1 (ICAM-1). Selective COX-2 inhibitors (celecoxib and NS-398) protected against the development of steatohepatitis in WT but not PPAR-alpha-/- mice. In conclusion, induction of COX-2 occurs in association with NF-kappaB activation and upregulation of TNF-alpha, IL-6, and ICAM-1 in MCD diet-induced steatohepatitis. PPAR-alpha suppresses both COX-2 and development of steatohepatitis, while pharmacological inhibition of COX-2 activity ameliorates the severity of experimental steatohepatitis. COX-2 may therefore be a pro-inflammatory mediator in metabolic forms of steatohepatitis.

Animals↗
PubMed2005

Phosphatidylcholine and lysophosphatidylcholine excretion is increased in children with cystic fibrosis and is associated with plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine.

BACKGROUND: Hepatic steatosis and fat malabsorption are common in cystic fibrosis (CF). Choline deficiency results in decreased phosphatidylcholine synthesis through the cytidine diphosphocholine-choline pathway and hepatic steatosis and in increased synthesis of phosphatidylcholine from phosphatidylethanolamine using methyl groups from S-adenosylmethionine. The intestinal absorption of phosphatidylcholine in CF is unknown. OBJECTIVES: The objective was to determine whether excretion of choline phosphoglyceride (phosphatidylcholine and lysophosphatidylcholine) is increased in CF and whether loss of fecal choline phosphoglyceride is associated with altered plasma methionine cycle metabolites. DESIGN: A cross-sectional study involved 53 children with CF and 18 control children without CF. Blood was collected from all participants. A subset of 18 children with CF and 8 control children provided 72-h fecal samples and 5-d food records. RESULTS: Fat absorption was significantly lower (x+/- SEM: 86.2 +/- 1.6% and 94.1 +/- 1.2%) and excretion of fecal fat (12.9 +/- 1.7 and 3.9 +/- 0.7 g/d), phospholipid (median: 130 and 47.7 mg/d), phosphatidylcholine (19.6 and 2.1 mg/d), and lysophosphatidylcholine (60.3 and 16.9 mg/d) was significantly higher in children with CF than in control children, respectively (P < 0.05). Choline phosphoglyceride excretion was positively correlated with plasma homocysteine and S-adenosylhomocysteine and inversely related with plasma methionine (P < 0.05). CONCLUSIONS: Choline phosphoglyceride excretion is increased in children with CF and is associated with decreased plasma methionine and increased homocysteine and S-adenosylhomocysteine. These findings suggest choline depletion and an increased choline synthesis by S-adenosylmethionine-dependent methylation in CF, as well as a metabolic link between phosphatidylcholine metabolism and the methionine-homocysteine cycle in humans.

Case-Control Studies↗
PubMed1985

Concentration-dependent inhibition of development of GGT positive foci in rat liver by the environmental contaminant di(2-ethylhexyl) phthalate.

The ability of di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer and environmental contaminant, to suppress development of putative preneoplastic lesions in rat liver was evaluated. gamma-Glutamyl transpeptidase-positive (GGT+) foci were initiated in the livers of Sprague-Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. Promotion of foci was commenced by feeding a choline-deficient diet (CD). A group of control rats was fed a choline-supplemented diet (CS). The ability of DEHP to suppress the emergence of GGT+ foci was evaluated by feeding additional groups of rats the CD diet containing either 0.1%, 0.5%, 1.0% or 2.0% DEHP. The CD diet promoted the number of GGT+ foci above levels in control livers. Inclusion of the plasticizer to the levels of 0.5%, 1.0% and 2.0% in the CD diet effectively inhibited the appearance of the foci. However, DEHP was unable to inhibit the promoting effect of the CD diet at a concentration of 0.1%. DEHP's ability to block development of GGT+ foci correlated with its ability to increase liver weight and to induce carnitine acetyltransferase (EC 2.3.1.7), a marker of peroxisome proliferation.

Animals↗