The lipid transporter Mfsd2a maintains pulmonary surfactant homeostasis

Wong, Bernice H.; Ding, Mei; Chua, Geok Lin; Galam, Dwight L.A.; Wenk, Markus R.; Torta, Federico; Silver, David L.

doi:10.1016/j.jbc.2022.101709

Cited by 11 publications

(12 citation statements)

References 65 publications

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“…Sample preparation for lipidomics is described in SI Appendix , Supplementary Methods . The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and data analysis were performed as previously reported ( 45 ). Targeted analysis was performed in dynamic multiple reaction monitoring MS-positive and -negative (only when measuring LPA species) ion mode.…”

Section: Methodsmentioning

confidence: 99%

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage

Kuk

Ding³

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.

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Section: Methodsmentioning

confidence: 99%

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage

Kuk

Ding³

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in ABCA3 result in chronic surfactant insufficiency and decrease PL in bronchoalveolar lavage ( Beers et al, 2017 ). Inhibition of Mfsd2a in AE2 cells results in hypertrophy, a lack of steady-state surfactant levels, and alteration in surfactant lipid composition ( Wong et al, 2022 ). Since Mfsd2a plays an important role in maintaining surfactant homeostasis, it remains to be determined whether it can play a role in pulmonary fibrosis.…”

Section: Alveolar Epithelial Cellsmentioning

confidence: 99%

Metabolic reprogramming of pulmonary fibrosis

Zhai²,

Sun³

et al. 2022

Front. Pharmacol.

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Pulmonary fibrosis is a progressive and intractable lung disease with fibrotic features that affects alveoli elasticity, which leading to higher rates of hospitalization and mortality worldwide. Pulmonary fibrosis is initiated by repetitive localized micro-damages of the alveolar epithelium, which subsequently triggers aberrant epithelial-fibroblast communication and myofibroblasts production in the extracellular matrix, resulting in massive extracellular matrix accumulation and interstitial remodeling. The major cell types responsible for pulmonary fibrosis are myofibroblasts, alveolar epithelial cells, macrophages, and endothelial cells. Recent studies have demonstrated that metabolic reprogramming or dysregulation of these cells exerts their profibrotic role via affecting pathological mechanisms such as autophagy, apoptosis, aging, and inflammatory responses, which ultimately contributes to the development of pulmonary fibrosis. This review summarizes recent findings on metabolic reprogramming that occur in the aforementioned cells during pulmonary fibrosis, especially those associated with glucose, lipid, and amino acid metabolism, with the aim of identifying novel treatment targets for pulmonary fibrosis.

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“…9,10 Pulmonary surfactants play an important role in maintaining pulmonary physiological function and preventing lung diseases such as acute respiratory distress syndrome, idiopathic pulmonary fibrosis and COPD. 10 Cholesterol, as a crucial lipid in both blood and pulmonary surfactants, has been reported to contribute to several pulmonary diseases. [11][12][13] The level of cholesterol is positively related to the severity of COPD, although the underlying mechanisms are still unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Epithelial cells, the first defense barrier of the respiratory system against hazardous substances, are in contact with pulmonary surfactants containing abundant lipids. Of those, dipalmitoyl‐phosphatidylcholine was found to be the most abundant lipid that could be absorbed and secreted by the epithelium 9,10 . Pulmonary surfactants play an important role in maintaining pulmonary physiological function and preventing lung diseases such as acute respiratory distress syndrome, idiopathic pulmonary fibrosis and COPD 10 .…”

Section: Introductionmentioning

confidence: 99%

“…Of those, dipalmitoyl‐phosphatidylcholine was found to be the most abundant lipid that could be absorbed and secreted by the epithelium 9,10 . Pulmonary surfactants play an important role in maintaining pulmonary physiological function and preventing lung diseases such as acute respiratory distress syndrome, idiopathic pulmonary fibrosis and COPD 10 . Cholesterol, as a crucial lipid in both blood and pulmonary surfactants, has been reported to contribute to several pulmonary diseases 11–13 .…”

Section: Introductionmentioning

confidence: 99%

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The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases

Wang

2022

Clinical and Translational Dis

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With the development of lipidomics, the significance of lipid metabolism in various lung diseases has been noticed recently. Among them, cholesterol metabolism plays a crucial role in the pathological process of chronic obstructive pulmonary diseases (COPD). Cholesterol accumulation could lead to mitochondrial dysfunction, such as impaired respiration, imbalanced dynamics and decreased adenosine triphosphate production, while mitochondrial dysfunction, especially altered mitochondrial dynamics, could also disrupt lipid homeostasis in cells. This review focuses on cholesterol metabolism and mitochondrial function in COPD and discusses the potential mechanisms of the steroidogenic acute regulatory-related lipid transfer domain family (STARD), especially STARD3. The review provides new insights for understanding the pathological process between STARD and mitochondria and new therapeutic targets in COPD.

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The lipid transporter Mfsd2a maintains pulmonary surfactant homeostasis

Cited by 11 publications

References 65 publications

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage

Metabolic reprogramming of pulmonary fibrosis

The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases

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