An Experimental DUAL Model of Advanced Liver Damage

Benedé-Ubieto, Raquel; Estévez-Vázquez, Olga; Guo, Feifei; Chen, Chaobo; Singh, Youvika; Nakaya, Helder I.; Gómez del Moral, Manuel; Lamas-Paz, Arantza; Morán, Laura; López-Alcántara, Nuria; Reissing, Johanna; Bruns, Tony; Ávila, Matías A.; Santamaría, Eva M.; Mazariegos, Marina S.; Woitok, Marius Maximilian; Haas, Ute; Zheng, Kang; Juárez, Ignacio; Martín-Villa, José Manuel; Asensio, Iris; Vaquero, Javier; Peligros, María Isabel; Argemi, Josepmaria; Bataller, Ramón; Ampuero, Javier; Romero-Gómez, Manuel; Trautwein, Christian; Liedtke, Christian; Bañares, Rafael; Cubero, Javier; Nevzorova, Yulia A.

An Experimental DUAL Model of Advanced Liver Damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing...

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Detalhes bibliográficos
Autores:	Benedé-Ubieto, Raquel, Estévez-Vázquez, Olga, Guo, Feifei, Chen, Chaobo, Singh, Youvika, Nakaya, Helder I., Gómez del Moral, Manuel, Lamas-Paz, Arantza, Morán, Laura, López-Alcántara, Nuria, Reissing, Johanna, Bruns, Tony, Ávila, Matías A., Santamaría, Eva M., Mazariegos, Marina S., Woitok, Marius Maximilian, Haas, Ute, Zheng, Kang, Juárez, Ignacio, Martín-Villa, José Manuel, Asensio, Iris, Vaquero, Javier, Peligros, María Isabel, Argemi, Josepmaria, Bataller, Ramón, Ampuero, Javier, Romero-Gómez, Manuel, Trautwein, Christian, Liedtke, Christian, Bañares, Rafael, Cubero, Javier, Nevzorova, Yulia A.
Formato:	artículo
Estado:	Versión publicada
Fecha de publicación:	2021
País:	España
Recursos:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/266047
Acesso em linha:	http://hdl.handle.net/10261/266047
Access Level:	acceso abierto

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network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	An Experimental DUAL Model of Advanced Liver Damage
title	An Experimental DUAL Model of Advanced Liver Damage
spellingShingle	An Experimental DUAL Model of Advanced Liver Damage Benedé-Ubieto, Raquel
title_short	An Experimental DUAL Model of Advanced Liver Damage
title_full	An Experimental DUAL Model of Advanced Liver Damage
title_fullStr	An Experimental DUAL Model of Advanced Liver Damage
title_full_unstemmed	An Experimental DUAL Model of Advanced Liver Damage
title_sort	An Experimental DUAL Model of Advanced Liver Damage
dc.creator.none.fl_str_mv	Benedé-Ubieto, Raquel Estévez-Vázquez, Olga Guo, Feifei Chen, Chaobo Singh, Youvika Nakaya, Helder I. Gómez del Moral, Manuel Lamas-Paz, Arantza Morán, Laura López-Alcántara, Nuria Reissing, Johanna Bruns, Tony Ávila, Matías A. Santamaría, Eva M. Mazariegos, Marina S. Woitok, Marius Maximilian Haas, Ute Zheng, Kang Juárez, Ignacio Martín-Villa, José Manuel Asensio, Iris Vaquero, Javier Peligros, María Isabel Argemi, Josepmaria Bataller, Ramón Ampuero, Javier Romero-Gómez, Manuel Trautwein, Christian Liedtke, Christian Bañares, Rafael Cubero, Javier Nevzorova, Yulia A.
author	Benedé-Ubieto, Raquel
author_facet	Benedé-Ubieto, Raquel Estévez-Vázquez, Olga Guo, Feifei Chen, Chaobo Singh, Youvika Nakaya, Helder I. Gómez del Moral, Manuel Lamas-Paz, Arantza Morán, Laura López-Alcántara, Nuria Reissing, Johanna Bruns, Tony Ávila, Matías A. Santamaría, Eva M. Mazariegos, Marina S. Woitok, Marius Maximilian Haas, Ute Zheng, Kang Juárez, Ignacio Martín-Villa, José Manuel Asensio, Iris Vaquero, Javier Peligros, María Isabel Argemi, Josepmaria Bataller, Ramón Ampuero, Javier Romero-Gómez, Manuel Trautwein, Christian Liedtke, Christian Bañares, Rafael Cubero, Javier Nevzorova, Yulia A.
author_role	author
author2	Estévez-Vázquez, Olga Guo, Feifei Chen, Chaobo Singh, Youvika Nakaya, Helder I. Gómez del Moral, Manuel Lamas-Paz, Arantza Morán, Laura López-Alcántara, Nuria Reissing, Johanna Bruns, Tony Ávila, Matías A. Santamaría, Eva M. Mazariegos, Marina S. Woitok, Marius Maximilian Haas, Ute Zheng, Kang Juárez, Ignacio Martín-Villa, José Manuel Asensio, Iris Vaquero, Javier Peligros, María Isabel Argemi, Josepmaria Bataller, Ramón Ampuero, Javier Romero-Gómez, Manuel Trautwein, Christian Liedtke, Christian Bañares, Rafael Cubero, Javier Nevzorova, Yulia A.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Comunidad de Madrid Ministerio de Economía y Competitividad (España) German Research Foundation Gilead Sciences China Scholarship Council Universidad Complutense de Madrid Banco Santander Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description	Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
publishDate	2021
dc.date.none.fl_str_mv	2021 2022 2022 2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/266047
url	http://hdl.handle.net/10261/266047
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# S2017/BMD-3727/EXOHEP-CM Y2018/NMT-4949/NanoLiver-CM info:eu-repo/grantAgreement/MINECO//RYC-2014-15242 info:eu-repo/grantAgreement/MINECO//RYC-2015-17438 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87919-R info:eu-repo/grantAgreement/MINECO//SAF2016-78711 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87919-R http://dx.doi.org/10.1002/hep4.1698 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	John Wiley & Sons
publisher.none.fl_str_mv	John Wiley & Sons
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling	An Experimental DUAL Model of Advanced Liver DamageBenedé-Ubieto, RaquelEstévez-Vázquez, OlgaGuo, FeifeiChen, ChaoboSingh, YouvikaNakaya, Helder I.Gómez del Moral, ManuelLamas-Paz, ArantzaMorán, LauraLópez-Alcántara, NuriaReissing, JohannaBruns, TonyÁvila, Matías A.Santamaría, Eva M.Mazariegos, Marina S.Woitok, Marius MaximilianHaas, UteZheng, KangJuárez, IgnacioMartín-Villa, José ManuelAsensio, IrisVaquero, JavierPeligros, María IsabelArgemi, JosepmariaBataller, RamónAmpuero, JavierRomero-Gómez, ManuelTrautwein, ChristianLiedtke, ChristianBañares, RafaelCubero, JavierNevzorova, Yulia A.Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.Supported by EXOHEP-CM (S2017/BMD-3727), Ramón y Cajal (RYC-2014-15242 and RYC-2015-17438), NanoLiver-CM (Y2018/NMT-4949), COST Action (CA17112), AMMF (2018/117), ERAB (EA 18/14), MINECO Retos (SAF2016-78711 and SAF2017-87919-R), and German Research Foundation (DFG NE 2128/2-1, SFB 1382-403224013/A02, and SFB/TRR57/P04). FJC is a Gilead Research Liver Scholar. The research group belongs to the validated Research group Ref. 970935 “Liver Pathophysiology”, 920631 “Lymphocyte immunology”, 920361 “Immunogenética e inmunología de las mucosas” and IBL-6 (imas12-associated). FG and KZ are Chinese Scholarship Council (CSC) fellows. O.E.-V is supported by Beca FPI (associated to MINECO SAF2017-87919R) and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19).John Wiley & SonsComunidad de MadridMinisterio de Economía y Competitividad (España)German Research FoundationGilead SciencesChina Scholarship CouncilUniversidad Complutense de MadridBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/266047reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#S2017/BMD-3727/EXOHEP-CMY2018/NMT-4949/NanoLiver-CMinfo:eu-repo/grantAgreement/MINECO//RYC-2014-15242info:eu-repo/grantAgreement/MINECO//RYC-2015-17438info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87919-Rinfo:eu-repo/grantAgreement/MINECO//SAF2016-78711info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87919-Rhttp://dx.doi.org/10.1002/hep4.1698Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2660472026-05-22T06:33:51Z
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An Experimental DUAL Model of Advanced Liver Damage

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