Regulation of Surfactant-Associated Phospholipid Synthesis and Secretion

Bernhard, Wolfgang

doi:10.1016/b978-0-323-35214-7.00082-2

Cited by 4 publications

(4 citation statements)

References 270 publications

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“…The assembly of the lamellar bodies is mediated by ATP‐binding cassette transporters. After their assembly in the endoplasmatic reticulum, lamellar bodies containing the surfactant fuse with the apical plasma membrane and release the content into the lumen of the alveolus in a Ca + dependent manner [47].…”

Section: Alveolar Cell Biologymentioning

confidence: 99%

Alveolar progenitor cells and the origin of lung cancer

2020

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Lung Cancer is the leading cause of cancer-related deaths worldwide. This is mainly due to late diagnosis and therefore advanced stage of the disease. Understanding the cell of origin of cancer and the processes that lead to its transformation will allow for earlier diagnosis and more accurate prediction of tumour type, ultimately leading to better treatments and lower patient morbidity. In this review, we focus on alveolar type 2 (AT2) cells as the cell of origin of lung adenocarcinoma (LUAD), the most common type of lung cancer. We first elaborate on the different oncogenes that are associated with LUAD and other lung cancers. After, we lay out in detail what is known about AT2 biology, to further delve into AT2 cells as cell of origin for adenocarcinoma. Understanding the precursors of LUAD and identifying the molecular changes during its progression will allow for earlier detection and better molecular targeting of the disease in early stages.

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Section: Alveolar Cell Biologymentioning

confidence: 99%

Alveolar progenitor cells and the origin of lung cancer

2020

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“…The metabolic consumption of D9-betaine for D3-SAM synthesis is confirmed by the presence of D6-dimethylglycine (D6-DMG), D3-methionine, D3-PC derived from the PEMT pathway and free D3-choline [ 22 ]. However, total amounts of D3-PC and D3-choline were low compared to D9-PC and D9-betaine, suggesting low activity of this pathway in neonatal rats, as also found in choline-deficient preterm infants [ 24 , 53 ]. Nevertheless, such low PEMT activity still contributes to DHA-PC formation in choline-supplemented preterm infants [ 24 ].…”

Section: Discussionmentioning

confidence: 93%

“…Similar to the liver, apical surfactant secretion is separated from basolateral PC secretion contributing to systemic lipid homeostasis (see above). This is analogous to the separation of apical hepatic PC secretion into bile (and its enterohepatic cycle) from the liver’s contribution to systemic PC metabolism [ 53 ]. However, whereas apical secretion of the liver into bile consumes at least 50% of its PC pool per day, surfactant secretion consumes only a minor fraction of pulmonary PC synthesis [ 28 , 51 ], suggesting that choline requirements of the lungs are dominated by its parenchymal requirement and contribution to systemic lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Choline Kinetics in Neonatal Liver, Brain and Lung—Lessons from a Rodent Model for Neonatal Care

et al. 2022

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Choline requirements are high in the rapidly growing fetus and preterm infant, mainly serving phosphatidylcholine (PC) synthesis for parenchymal growth and one-carbon metabolism via betaine. However, choline metabolism in critical organs during rapid growth is poorly understood. Therefore, we investigated the kinetics of D9-choline and its metabolites in the liver, plasma, brain and lung in 14 d old rats. Animals were intraperitoneally injected with 50 mg/kg D9-choline chloride and sacrificed after 1.5 h, 6 h and 24 h. Liver, plasma, lungs, cerebrum and cerebellum were analyzed for D9-choline metabolites, using tandem mass spectrometry. In target organs, D9-PC and D9-betaine comprised 15.1 ± 1.3% and 9.9 ± 1.2% of applied D9-choline at 1.5 h. D9-PC peaked at 1.5 h in all organs, and decreased from 1.5–6 h in the liver and lung, but not in the brain. Whereas D9-labeled PC precursors were virtually absent beyond 6 h, D9-PC increased in the brain and lung from 6 h to 24 h (9- and 2.5-fold, respectively) at the expense of the liver, suggesting PC uptake from the liver via plasma rather than local synthesis. Kinetics of D9-PC sub-groups suggested preferential hepatic secretion of linoleoyl-PC and acyl remodeling in target organs. D9-betaine showed rapid turnover and served low-level endogenous (D3-)choline synthesis. In conclusion, in neonatal rats, exogenous choline is rapidly metabolized to PC by all organs. The liver supplies the brain and lung directly with PC, followed by organotypic acyl remodeling. A major fraction of choline is converted to betaine, feeding the one-carbon pool and this must be taken into account when calculating choline requirements.

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“…The mechanisms involved, however, require further investigation, but may relate to the improved choline availability of the lungs. In this organ, PC is exclusively synthesized de novo from exogenous choline uptake, proportional to its extracellular concentration [15,35,36,38]. Beyond its functions in membranes and surfactant, and its secretion into the circulation, via basolateral ATP-binding cassette transporter A1 (ABC-A1), to feed systemic lipoprotein homeostasis and the liver in choline deficiency [22,23,24,25], PC serves to remove pro-apoptotic ceramides via sphingomyelin (SPM) synthase (EC2.7.8.27) [3].…”

Section: Discussionmentioning

confidence: 99%

Choline Supplementation in Cystic Fibrosis—The Metabolic and Clinical Impact

et al. 2019

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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.

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Regulation of Surfactant-Associated Phospholipid Synthesis and Secretion

Cited by 4 publications

References 270 publications

Alveolar progenitor cells and the origin of lung cancer

Alveolar progenitor cells and the origin of lung cancer

Choline Kinetics in Neonatal Liver, Brain and Lung—Lessons from a Rodent Model for Neonatal Care

Choline Supplementation in Cystic Fibrosis—The Metabolic and Clinical Impact

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