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Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis

Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled cr...

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Autores principales: Padiadpu, Jyothi, Garcia‐Jaramillo, Manuel, Newman, Nolan K, Pederson, Jacob W, Rodrigues, Richard, Li, Zhipeng, Singh, Sehajvir, Monnier, Philip, Trinchieri, Giorgio, Brown, Kevin, Dzutsev, Amiran K, Shulzhenko, Natalia, Jump, Donald B, Morgun, Andrey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630881/
https://www.ncbi.nlm.nih.gov/pubmed/37859621
http://dx.doi.org/10.15252/emmm.202318367
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author Padiadpu, Jyothi
Garcia‐Jaramillo, Manuel
Newman, Nolan K
Pederson, Jacob W
Rodrigues, Richard
Li, Zhipeng
Singh, Sehajvir
Monnier, Philip
Trinchieri, Giorgio
Brown, Kevin
Dzutsev, Amiran K
Shulzhenko, Natalia
Jump, Donald B
Morgun, Andrey
author_facet Padiadpu, Jyothi
Garcia‐Jaramillo, Manuel
Newman, Nolan K
Pederson, Jacob W
Rodrigues, Richard
Li, Zhipeng
Singh, Sehajvir
Monnier, Philip
Trinchieri, Giorgio
Brown, Kevin
Dzutsev, Amiran K
Shulzhenko, Natalia
Jump, Donald B
Morgun, Andrey
author_sort Padiadpu, Jyothi
collection PubMed
description Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta‐analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR‐binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti‐inflammatory and anti‐fibrotic effects of ω3 PUFA on NASH.
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spelling pubmed-106308812023-11-15 Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis Padiadpu, Jyothi Garcia‐Jaramillo, Manuel Newman, Nolan K Pederson, Jacob W Rodrigues, Richard Li, Zhipeng Singh, Sehajvir Monnier, Philip Trinchieri, Giorgio Brown, Kevin Dzutsev, Amiran K Shulzhenko, Natalia Jump, Donald B Morgun, Andrey EMBO Mol Med Articles Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta‐analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR‐binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti‐inflammatory and anti‐fibrotic effects of ω3 PUFA on NASH. John Wiley and Sons Inc. 2023-10-20 /pmc/articles/PMC10630881/ /pubmed/37859621 http://dx.doi.org/10.15252/emmm.202318367 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Padiadpu, Jyothi
Garcia‐Jaramillo, Manuel
Newman, Nolan K
Pederson, Jacob W
Rodrigues, Richard
Li, Zhipeng
Singh, Sehajvir
Monnier, Philip
Trinchieri, Giorgio
Brown, Kevin
Dzutsev, Amiran K
Shulzhenko, Natalia
Jump, Donald B
Morgun, Andrey
Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title_full Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title_fullStr Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title_full_unstemmed Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title_short Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
title_sort multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630881/
https://www.ncbi.nlm.nih.gov/pubmed/37859621
http://dx.doi.org/10.15252/emmm.202318367
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