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Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver‐specific enzyme, inhibits oxidation of phospholipids and prevents lipid‐mediated oxidative damage....

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Autores principales: Maras, Jaswinder Singh, Das, Sukanta, Bhat, Adil, Kumar Vyas, Ashish, Yadav, Gaurav, Chaudhary, Sudrishti, Sukriti, Sukriti, Gupta, Abhishak C., Bihari, Chagan, Mahiwall, Rakhi, Sarin, Shiv Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887666/
https://www.ncbi.nlm.nih.gov/pubmed/31832570
http://dx.doi.org/10.1002/hep4.1438
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author Maras, Jaswinder Singh
Das, Sukanta
Bhat, Adil
Kumar Vyas, Ashish
Yadav, Gaurav
Chaudhary, Sudrishti
Sukriti, Sukriti
Gupta, Abhishak C.
Bihari, Chagan
Mahiwall, Rakhi
Sarin, Shiv Kumar
author_facet Maras, Jaswinder Singh
Das, Sukanta
Bhat, Adil
Kumar Vyas, Ashish
Yadav, Gaurav
Chaudhary, Sudrishti
Sukriti, Sukriti
Gupta, Abhishak C.
Bihari, Chagan
Mahiwall, Rakhi
Sarin, Shiv Kumar
author_sort Maras, Jaswinder Singh
collection PubMed
description Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver‐specific enzyme, inhibits oxidation of phospholipids and prevents lipid‐mediated oxidative damage. However, its functional contribution in macrophage‐mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku‐Hospital‐Pediatrics‐1 (THP1)‐derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up‐regulated and 176 down‐regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r(2) > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut‐off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low‐density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate‐binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28‐day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.
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spelling pubmed-68876662019-12-12 Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis Maras, Jaswinder Singh Das, Sukanta Bhat, Adil Kumar Vyas, Ashish Yadav, Gaurav Chaudhary, Sudrishti Sukriti, Sukriti Gupta, Abhishak C. Bihari, Chagan Mahiwall, Rakhi Sarin, Shiv Kumar Hepatol Commun Original Articles Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver‐specific enzyme, inhibits oxidation of phospholipids and prevents lipid‐mediated oxidative damage. However, its functional contribution in macrophage‐mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku‐Hospital‐Pediatrics‐1 (THP1)‐derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up‐regulated and 176 down‐regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r(2) > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut‐off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low‐density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate‐binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28‐day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH. John Wiley and Sons Inc. 2019-10-30 /pmc/articles/PMC6887666/ /pubmed/31832570 http://dx.doi.org/10.1002/hep4.1438 Text en © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Maras, Jaswinder Singh
Das, Sukanta
Bhat, Adil
Kumar Vyas, Ashish
Yadav, Gaurav
Chaudhary, Sudrishti
Sukriti, Sukriti
Gupta, Abhishak C.
Bihari, Chagan
Mahiwall, Rakhi
Sarin, Shiv Kumar
Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title_full Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title_fullStr Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title_full_unstemmed Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title_short Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis
title_sort dysregulated lipid transport proteins correlate with pathogenesis and outcome in severe alcoholic hepatitis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887666/
https://www.ncbi.nlm.nih.gov/pubmed/31832570
http://dx.doi.org/10.1002/hep4.1438
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