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Hepatic steatosis accompanies pulmonary alveolar proteinosis

Hepatic steatosis accompanies pulmonary alveolar proteinosis
Hepatic steatosis accompanies pulmonary alveolar proteinosis
Maintenance of tissue-specific organ lipid compositions characterises mammalian lipid homeostasis. Lung and liver synthesise mixed phosphatidylcholine (PC) molecular species subsequently “tailored” for function. Lungs progressively enrich disaturated PC (DSPC) directed to lamellar body (LB) surfactant stores prior to secretion. Liver accumulates polyunsaturated PC directed to VLDL assembly and secretion, or triglyceride stores. In each tissue, selective PC species enrichment mechanisms lie at the heart of effective homeostasis. We tested potential coordination between these spatially separated, but possibly complementary phenomena under a major derangement of lung PC metabolism, Pulmonary Alveolar Proteinosis (PAP), which overwhelms homeostasis leading to excessive surfactant accumulation. Using static and dynamic lipidomics techniques we compared (i) tissue PC compositions and contents and (ii) in lungs, the absolute rates of synthesis from both control mice and the GM-CSF knockout model of PAP. Significant DSPC accumulation in BALF, Alveolar Macrophage (AM) and lavaged lung tissue occurred alongside increased PC synthesis consistent with reported defects in AM surfactant turnover. However, microscopy using oil red O staining, CARS, SHG and TEM also revealed neutral lipid droplet accumulations in alveolar lipofibroblasts of GM-CSF KO animals suggesting lipid homeostasis deficits extend beyond AMs. PAP plasma PC composition was significantly PUFA-enriched but content was unchanged and hepatic PUFA-enriched PC content increased by 50% with an accompanying micro/macrovesicular steatosis and a fibrotic damage pattern consistent with NAFLD. These data suggest a hepato-pulmonary axis of PC metabolism coordination with wider implications for understanding and managing lipid pathologies where compromise of one organ has unexpected consequences for another.
Phosphatidylcholine, phosphatidylcholine biosynthesis, phosphatidylcholine molecular species, Pulmonary surfactant, lipidomics, liver fibrosis, Lipotoxicity, Pulmonary Alveolar Proteinosis, steatosis, CARS microscopy
1044-1549
448-458
Hunt, Alan
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Malur, Anagha
ea1311b2-3801-429f-b2d0-eac972027bc0
Monfort, Tual, Remy
ddf9e1cd-1c31-4ca5-8f4f-d2efaab0c2f8
Lagoudakis, Pavlos
ea50c228-f006-4edf-8459-60015d961bbf
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Postle, Anthony
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Thomassen, Mary Jane
af68a6fd-42c9-4736-a2b8-b0691933d904
Hunt, Alan
95a3e223-da96-40e7-b47d-27dce014e305
Malur, Anagha
ea1311b2-3801-429f-b2d0-eac972027bc0
Monfort, Tual, Remy
ddf9e1cd-1c31-4ca5-8f4f-d2efaab0c2f8
Lagoudakis, Pavlos
ea50c228-f006-4edf-8459-60015d961bbf
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Postle, Anthony
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Thomassen, Mary Jane
af68a6fd-42c9-4736-a2b8-b0691933d904

Hunt, Alan, Malur, Anagha, Monfort, Tual, Remy, Lagoudakis, Pavlos, Mahajan, Sumeet, Postle, Anthony and Thomassen, Mary Jane (2017) Hepatic steatosis accompanies pulmonary alveolar proteinosis. American Journal of Respiratory Cell and Molecular Biology, 57 (4), 448-458. (doi:10.1165/rcmb.2016-0242OC).

Record type: Article

Abstract

Maintenance of tissue-specific organ lipid compositions characterises mammalian lipid homeostasis. Lung and liver synthesise mixed phosphatidylcholine (PC) molecular species subsequently “tailored” for function. Lungs progressively enrich disaturated PC (DSPC) directed to lamellar body (LB) surfactant stores prior to secretion. Liver accumulates polyunsaturated PC directed to VLDL assembly and secretion, or triglyceride stores. In each tissue, selective PC species enrichment mechanisms lie at the heart of effective homeostasis. We tested potential coordination between these spatially separated, but possibly complementary phenomena under a major derangement of lung PC metabolism, Pulmonary Alveolar Proteinosis (PAP), which overwhelms homeostasis leading to excessive surfactant accumulation. Using static and dynamic lipidomics techniques we compared (i) tissue PC compositions and contents and (ii) in lungs, the absolute rates of synthesis from both control mice and the GM-CSF knockout model of PAP. Significant DSPC accumulation in BALF, Alveolar Macrophage (AM) and lavaged lung tissue occurred alongside increased PC synthesis consistent with reported defects in AM surfactant turnover. However, microscopy using oil red O staining, CARS, SHG and TEM also revealed neutral lipid droplet accumulations in alveolar lipofibroblasts of GM-CSF KO animals suggesting lipid homeostasis deficits extend beyond AMs. PAP plasma PC composition was significantly PUFA-enriched but content was unchanged and hepatic PUFA-enriched PC content increased by 50% with an accompanying micro/macrovesicular steatosis and a fibrotic damage pattern consistent with NAFLD. These data suggest a hepato-pulmonary axis of PC metabolism coordination with wider implications for understanding and managing lipid pathologies where compromise of one organ has unexpected consequences for another.

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rcmb.2016-0242oc(1) - Accepted Manuscript
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Accepted/In Press date: 5 May 2017
e-pub ahead of print date: 10 May 2017
Published date: 1 October 2017
Keywords: Phosphatidylcholine, phosphatidylcholine biosynthesis, phosphatidylcholine molecular species, Pulmonary surfactant, lipidomics, liver fibrosis, Lipotoxicity, Pulmonary Alveolar Proteinosis, steatosis, CARS microscopy
Organisations: Institute for Life Sciences, Quantum, Light & Matter Group, Clinical & Experimental Sciences

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Local EPrints ID: 410603
URI: https://eprints.soton.ac.uk/id/eprint/410603
ISSN: 1044-1549
PURE UUID: 6e3ce69d-986a-48b8-8350-c00afea2bd00
ORCID for Alan Hunt: ORCID iD orcid.org/0000-0001-5938-2152
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666
ORCID for Anthony Postle: ORCID iD orcid.org/0000-0001-7361-0756

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Date deposited: 15 Feb 2018 17:32
Last modified: 03 Dec 2019 02:08

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Contributors

Author: Alan Hunt ORCID iD
Author: Anagha Malur
Author: Tual, Remy Monfort
Author: Sumeet Mahajan ORCID iD
Author: Anthony Postle ORCID iD
Author: Mary Jane Thomassen

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