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Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization...

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Autores principales: Ghallab, Ahmed, Myllys, Maiju, Friebel, Adrian, Duda, Julia, Edlund, Karolina, Halilbasic, Emina, Vucur, Mihael, Hobloss, Zaynab, Brackhagen, Lisa, Begher-Tibbe, Brigitte, Hassan, Reham, Burke, Michael, Genc, Erhan, Frohwein, Lynn Johann, Hofmann, Ute, Holland, Christian H., González, Daniela, Keller, Magdalena, Seddek, Abdel-latif, Abbas, Tahany, Mohammed, Elsayed S. I., Teufel, Andreas, Itzel, Timo, Metzler, Sarah, Marchan, Rosemarie, Cadenas, Cristina, Watzl, Carsten, Nitsche, Michael A., Kappenberg, Franziska, Luedde, Tom, Longerich, Thomas, Rahnenführer, Jörg, Hoehme, Stefan, Trauner, Michael, Hengstler, Jan G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533774/
https://www.ncbi.nlm.nih.gov/pubmed/34685496
http://dx.doi.org/10.3390/cells10102516
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author Ghallab, Ahmed
Myllys, Maiju
Friebel, Adrian
Duda, Julia
Edlund, Karolina
Halilbasic, Emina
Vucur, Mihael
Hobloss, Zaynab
Brackhagen, Lisa
Begher-Tibbe, Brigitte
Hassan, Reham
Burke, Michael
Genc, Erhan
Frohwein, Lynn Johann
Hofmann, Ute
Holland, Christian H.
González, Daniela
Keller, Magdalena
Seddek, Abdel-latif
Abbas, Tahany
Mohammed, Elsayed S. I.
Teufel, Andreas
Itzel, Timo
Metzler, Sarah
Marchan, Rosemarie
Cadenas, Cristina
Watzl, Carsten
Nitsche, Michael A.
Kappenberg, Franziska
Luedde, Tom
Longerich, Thomas
Rahnenführer, Jörg
Hoehme, Stefan
Trauner, Michael
Hengstler, Jan G.
author_facet Ghallab, Ahmed
Myllys, Maiju
Friebel, Adrian
Duda, Julia
Edlund, Karolina
Halilbasic, Emina
Vucur, Mihael
Hobloss, Zaynab
Brackhagen, Lisa
Begher-Tibbe, Brigitte
Hassan, Reham
Burke, Michael
Genc, Erhan
Frohwein, Lynn Johann
Hofmann, Ute
Holland, Christian H.
González, Daniela
Keller, Magdalena
Seddek, Abdel-latif
Abbas, Tahany
Mohammed, Elsayed S. I.
Teufel, Andreas
Itzel, Timo
Metzler, Sarah
Marchan, Rosemarie
Cadenas, Cristina
Watzl, Carsten
Nitsche, Michael A.
Kappenberg, Franziska
Luedde, Tom
Longerich, Thomas
Rahnenführer, Jörg
Hoehme, Stefan
Trauner, Michael
Hengstler, Jan G.
author_sort Ghallab, Ahmed
collection PubMed
description Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
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spelling pubmed-85337742021-10-23 Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression Ghallab, Ahmed Myllys, Maiju Friebel, Adrian Duda, Julia Edlund, Karolina Halilbasic, Emina Vucur, Mihael Hobloss, Zaynab Brackhagen, Lisa Begher-Tibbe, Brigitte Hassan, Reham Burke, Michael Genc, Erhan Frohwein, Lynn Johann Hofmann, Ute Holland, Christian H. González, Daniela Keller, Magdalena Seddek, Abdel-latif Abbas, Tahany Mohammed, Elsayed S. I. Teufel, Andreas Itzel, Timo Metzler, Sarah Marchan, Rosemarie Cadenas, Cristina Watzl, Carsten Nitsche, Michael A. Kappenberg, Franziska Luedde, Tom Longerich, Thomas Rahnenführer, Jörg Hoehme, Stefan Trauner, Michael Hengstler, Jan G. Cells Article Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets. MDPI 2021-09-23 /pmc/articles/PMC8533774/ /pubmed/34685496 http://dx.doi.org/10.3390/cells10102516 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ghallab, Ahmed
Myllys, Maiju
Friebel, Adrian
Duda, Julia
Edlund, Karolina
Halilbasic, Emina
Vucur, Mihael
Hobloss, Zaynab
Brackhagen, Lisa
Begher-Tibbe, Brigitte
Hassan, Reham
Burke, Michael
Genc, Erhan
Frohwein, Lynn Johann
Hofmann, Ute
Holland, Christian H.
González, Daniela
Keller, Magdalena
Seddek, Abdel-latif
Abbas, Tahany
Mohammed, Elsayed S. I.
Teufel, Andreas
Itzel, Timo
Metzler, Sarah
Marchan, Rosemarie
Cadenas, Cristina
Watzl, Carsten
Nitsche, Michael A.
Kappenberg, Franziska
Luedde, Tom
Longerich, Thomas
Rahnenführer, Jörg
Hoehme, Stefan
Trauner, Michael
Hengstler, Jan G.
Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title_full Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title_fullStr Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title_full_unstemmed Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title_short Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
title_sort spatio-temporal multiscale analysis of western diet-fed mice reveals a translationally relevant sequence of events during nafld progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533774/
https://www.ncbi.nlm.nih.gov/pubmed/34685496
http://dx.doi.org/10.3390/cells10102516
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