Abstract
Background: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. Methods: 10 adult male CF patients were recruited (11/2014–1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84–91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. Results: Supplementation increased plasma choline from 4.8 (4.1–6.2) µmol/L to 10.5 (8.5–15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5–18.3] µmol/L vs. 17.7 [15.5–22.4] µmol/L, p < 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9–74.8)% to 78.3 (60.1–83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37–8.82)% to 0.84 (0.56–1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. Conclusions: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.
Highlights
Cystic fibrosis (CF) is a recessive autosomal disease, caused by mutations of the Cystic FibrosisTransmembrane Conductance Regulator (CFTR) gene
As a primary outcome parameter, we investigated the effect of supplementation on plasma D9 -PC concentration, 33 h after [D9 -methyl]choline chloride administration
We further investigated whether choline supplementation increased plasma PC concentration We further investigated whether choline supplementation increased plasma PC concentration and influenced its metabolism in these patients
Summary
Cystic fibrosis (CF) is a recessive autosomal disease, caused by mutations of the Cystic FibrosisTransmembrane Conductance Regulator (CFTR) gene. Dysfunctional chloride and hydrogen carbonate transport in the lungs results in sticky airway secretions, with impaired mucociliary clearance, microbial colonization, inflammation, tissue degradation, and decline in lung function. Such a decline is linked to increased concentrations of pro-apoptotic ceramides, triggered by cleavage of the choline-containing phospholipid sphingomyelin (SPM) [1,2]. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9 ]choline chloride to assess choline/PC metabolism
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