Evidence of Choline Depletion and Reduced Betaine and Dimethylglycine with Increased Homocysteine in Plasma of Children with Cystic Fibrosis

Innis, Sheila M.; Hasman, David

doi:10.1093/jn/136.8.2226

Cited by 48 publications

(37 citation statements)

References 44 publications

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“…However, data on clinical improvements by docosahexaenoic acid (C22:6) are conflicting [22,28,29,30]. LC-PUFA metabolism is intimately linked to that of choline, since PC is a major LC-PUFA carrier between the liver and other organs.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, choline is a source to generate betaine, a methyl-group donator to regenerate methionine from homocysteine, the former being essential for the PEMT pathway [20,21]: the activated form of methionine, S-adenosyl-methionine (SAM), is co-substrate of PEMT for PC formation from polyunsaturated PE. Here, deficiency in methyl donators is consistent with decreased methionine and increased homocysteine concentrations in CF children [22,23]. Hence, fecal choline losses in CF may affect choline, one-carbon unit, PC and LC-PUFA homeostasis of the liver.…”

Section: Introductionmentioning

confidence: 87%

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Plasma Phosphatidylcholine Alterations in Cystic Fibrosis Patients: Impaired Metabolism and Correlation with Lung Function and Inflammation

Grothe

Riethmüller²,

Tschürtz³

et al. 2015

Cell Physiol Biochem

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Background: Liver impairment, ranging from steatosis to cirrhosis, is frequent in cystic fibrosis (CF) patients and is becoming increasingly significant due to their improved life expectancy. One aspect of hepatic alterations is caused by increased fecal loss of the essential nutrient choline, following enterohepatic bile phosphatidylcholine (PC) cycle impairment. Hepatic PC synthesis, both de novo and via phosphatidylethanolamine-N-methyl-transferase (PEMT), is essential for very low-density lipoprotein (VLDL) secretion. VLDL-PC in particular contributes to the organism's supply with polyunsaturated fatty acids (LC-PUFA), namely arachidonic (C20:4) and docosahexaenoic acid (C22:6). Consequently, choline deprivation and altered hepatic PC metabolism may affect plasma PC homeostasis and extrahepatic organ function. Objectives: To investigate relationships between altered plasma choline and PC homeostasis and markers of lung function and inflammation in CF. To assess alterations in hepatic choline and PC metabolism of CF patients. Design: Quantification of plasma/serum choline and PC species in adult CF patients compared to controls. Correlation of PC with forced expiratory vital capacity (FEV₁) and interleukin 6 (IL-6) concentrations. Analysis of choline and PC metabolism in CF compared to controls, using deuterated choline ([D₉-methyl]-choline) labeling in vivo. Results: Mean choline and PC concentrations in CF patients were lower than in controls. Choline and PC concentrations as well as fractions of C22:6-PC and C20:4-PC correlated directly with FEV₁, but inversely with IL-6. Plasma concentrations of deuterated PC were decreased for both pathways, whereas only in PC synthesized via PEMT precursor enrichment was decreased. Conclusion: In CF patients, hepatic and plasma homeostasis of choline and PC correlate with lung function and inflammation. Impaired hepatic PC metabolism, exemplarily shown in three CF patients, provides an explanation for such correlations. Larger studies are required to understand the link between hepatic PC metabolism and overall clinical performance of CF patients, and the perspective of choline substitution of these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Plasma Phosphatidylcholine Alterations in Cystic Fibrosis Patients: Impaired Metabolism and Correlation with Lung Function and Inflammation

Grothe

Riethmüller²,

Tschürtz³

et al. 2015

Cell Physiol Biochem

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“…These alterations include a decrease in circulating essential fatty acids ( 19,20 ), phospholipids, and lysophospholipids ( 21 ); decreased polyunsaturated fatty acids in lung, intestine, and pancreas of mice ( 22,23 ) and nasal cells of patients ( 24 ), mostly associated with an imbalanced n-3/n-6 ratio; and decreased linoleic acid ( 19,25 ) and lipoxin A4 in lung exudates from patients ( 26 ). These alterations have been attributed largely to malabsorption ( 19 ), increased fl ux through the n-6 biosynthetic pathway ( 25,27,28 ), and an alteration in the methionine-homocysteine cycle ( 29,30 ).…”

Section: Lc-msmentioning

confidence: 99%

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

Ollero

Astarita

Guerrera

et al. 2011

Journal of Lipid Research

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Cystic fi brosis (CF) is associated with abnormal lipid metabolism. We have recently shown variations in plasma levels of several phosphatidylcholine (PC) and lysophopshatidylcholine (LPC) species related to disease severity in CF patients. Here our goal was to search for blood plasma lipid signatures characteristic of CF patients bearing the same mutation (F508del) and different phenotypes, and to study their correlation with forced expiratory volume in 1 s (FEV1) and Pseudomonas aeruginosa chronic infection, evaluated at the time of testing (t = 0) and three years later (t = 3). Samples from 44 F508del homozygotes were subjected to a lipidomic approach based on LC-ESI-MS. Twelve free fatty acids were positively correlated with FEV1 at t = 0 (n = 29). Four of them (C20:3n-9, C20:5n-3, C22:5n-3, and C22:6n-3) were also positively correlated with FEV1 three years later, along with PC(32:2) and PC(36:4) (n = 31). Oleoylethanolamide (OEA) was negatively correlated with FEV1 progression (n = 17). Chronically infected patients at t = 0 showed lower PC(32:2), PC(38:5), and C18:3n-3 and higher cholesterol, cholesterol esters, and triacylglycerols (TAG). Chronically infected patients at t = 3 showed significantly lower levels of LPC(18:0). These results suggest a potential prognostic value for some lipid signatures in, to our knowledge, the fi rst longitudinal study aimed at identifying lipid biomarkers for CF. -Ollero, M., G. Astarita, I. C. Guerrera, I. Sermet-Gaudelus, S.

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“…Hepatocytes accumulate lipid when its synthesis, uptake, secretion and/or utilization are altered (Browning and Horton, 2004;Fromenty et al, 2004). Although the events that initiate most steatotic disorders are now beginning to be more clearly defined, it has been recognized for many years that methionine metabolism, which is altered in patients with alcoholic liver disease and other chronic liver disorders associated with steatosis, may play a contributory role (Diehl, 2005;Duong et al, 2006;Esfandiari et al, 2005;Innis and Hasman, 2006;Kharbanda, 2007;Lu et al, 2002;Mato et al, 2008;Wortham et al, 2008;Zhu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

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Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor Sadenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFα. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wildtype adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.

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Evidence of Choline Depletion and Reduced Betaine and Dimethylglycine with Increased Homocysteine in Plasma of Children with Cystic Fibrosis

Cited by 48 publications

References 44 publications

Plasma Phosphatidylcholine Alterations in Cystic Fibrosis Patients: Impaired Metabolism and Correlation with Lung Function and Inflammation

Plasma Phosphatidylcholine Alterations in Cystic Fibrosis Patients: Impaired Metabolism and Correlation with Lung Function and Inflammation

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

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