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

Abstract

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.

Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese

“…Depletion of PC has multiple deleterious effects on cellular physiology and promotes cell death and activation of inflammatory signaling (38)(39)(40)(41)(42). PC depletion has been implicated in the pathogenesis of NAFLD (17,18,43,44).…”

Endoplasmic reticulum stress and calcium imbalance are involved in cadmium-induced lipid aberrancy in Saccharomyces cerevisiae

“…In most of the species like yeast and plants, PC is a major acyl donor for triacylglycerol (TAG) synthesis via the activation of lecithin cholesterol acyltransferase (LRO1) (Dahlqvist et al 2000). The prominence of PC to health and disease was already proven by earlier studies (Farber et al 2000;Grothe et al 2015;Lee et al 2014). However, the metabolism under cellular stress remains unclear.…”

Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone

“…Consequently, the lung is integrated into systemic PC homeostasis, where plasma PC is a major component of lipoproteins (39). The relation between pulmonary and systemic PC metabolism was recently supported by the finding that plasma PC and choline concentrations correlate with lung function in cystic fibrosis patients (25). Hence, the integration of pulmonary PC into a systemic context may be relevant to neonates as well.…”

“…In this context it is important that choline as an essential nutrient to the lungs rapidly decreases in preterm infant plasma after birth, a general difference from neonatal lung injury models (9). Since choline and PC status of adult patients correlate with lung function (25), improved choline supply may be critical to pulmonary PC homeostasis in preterm infants.…”