Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation

Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoi...

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Autores: Alonso Peña, Marta, Espinosa Escudero, Ricardo, Hermanns, Heike M., Briz, Oscar, Herranz, José M., García Ruiz, Carmen, Fernández Checa Torres, José Carlos, Juamperez, Javier, Ávila, Matías, Argemí, Josep Maria, Bataller Alberola, Ramón, Crespo, Javier, Monte, María J., Geier, Andreas, Herraez, Elisa, Marín, José J. G.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/199557
Acesso em linha:https://hdl.handle.net/2445/199557
Access Level:acceso abierto
Palavra-chave:Malalties del fetge
Colesterol
Liver diseases
Cholesterol
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spelling Impact of Liver Inflammation on Bile Acid Side Chain Shortening and AmidationAlonso Peña, MartaEspinosa Escudero, RicardoHermanns, Heike M.Briz, OscarHerranz, José M.García Ruiz, CarmenFernández Checa Torres, José CarlosJuamperez, JavierÁvila, MatíasArgemí, Josep MariaBataller Alberola, RamónCrespo, JavierMonte, María J.Geier, AndreasHerraez, ElisaMarín, José J. G.Malalties del fetgeColesterolLiver diseasesCholesterolBile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4? (HNF4?) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7?-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4? levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile.MDPI2023202320222023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion20 p.application/pdfhttps://hdl.handle.net/2445/199557Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/cells11243983Cells, 2022, vol. 11, num. 24https://doi.org/10.3390/cells11243983cc by (c) Alonso Peña, Marta et al, 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1995572026-05-29T05:05:01Z
dc.title.none.fl_str_mv Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
title Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
spellingShingle Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
Alonso Peña, Marta
Malalties del fetge
Colesterol
Liver diseases
Cholesterol
title_short Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
title_full Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
title_fullStr Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
title_full_unstemmed Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
title_sort Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
dc.creator.none.fl_str_mv Alonso Peña, Marta
Espinosa Escudero, Ricardo
Hermanns, Heike M.
Briz, Oscar
Herranz, José M.
García Ruiz, Carmen
Fernández Checa Torres, José Carlos
Juamperez, Javier
Ávila, Matías
Argemí, Josep Maria
Bataller Alberola, Ramón
Crespo, Javier
Monte, María J.
Geier, Andreas
Herraez, Elisa
Marín, José J. G.
author Alonso Peña, Marta
author_facet Alonso Peña, Marta
Espinosa Escudero, Ricardo
Hermanns, Heike M.
Briz, Oscar
Herranz, José M.
García Ruiz, Carmen
Fernández Checa Torres, José Carlos
Juamperez, Javier
Ávila, Matías
Argemí, Josep Maria
Bataller Alberola, Ramón
Crespo, Javier
Monte, María J.
Geier, Andreas
Herraez, Elisa
Marín, José J. G.
author_role author
author2 Espinosa Escudero, Ricardo
Hermanns, Heike M.
Briz, Oscar
Herranz, José M.
García Ruiz, Carmen
Fernández Checa Torres, José Carlos
Juamperez, Javier
Ávila, Matías
Argemí, Josep Maria
Bataller Alberola, Ramón
Crespo, Javier
Monte, María J.
Geier, Andreas
Herraez, Elisa
Marín, José J. G.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties del fetge
Colesterol
Liver diseases
Cholesterol
topic Malalties del fetge
Colesterol
Liver diseases
Cholesterol
description Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4? (HNF4?) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7?-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4? levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/199557
url https://hdl.handle.net/2445/199557
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/cells11243983
Cells, 2022, vol. 11, num. 24
https://doi.org/10.3390/cells11243983
dc.rights.none.fl_str_mv cc by (c) Alonso Peña, Marta et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Alonso Peña, Marta et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 20 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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