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Structure-function analysis of time-resolved immunological phases in metabolic dysfunction-associated fatty liver disease (MASH) comparing the NIF mouse model to human MASH

Schmidt-Christensen, Anja LU orcid ; Eriksson, Gustaw LU ; Laprade, William M. ; Pirzamanbein, Behnaz LU orcid ; Hörnberg, Maria ; Linde, Kajsa ; Nilsson, Julia LU ; Skarsfeldt, Mark ; Leeming, Diana J. and Mokso, Rajmund LU , et al. (2024) In Scientific Reports 14(1).
Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a common but frequently unrecognized complication of obesity and type 2 diabetes. The association between these conditions is multifaceted and involves complex interactions between metabolic, inflammatory, and genetic factors. Here we assess the underlying structural and molecular processes focusing on the immunological phase of MASH in the nonobese inflammation and fibrosis (NIF) mouse model and compare it to the human disease as well as other murine models. Histopathology together with synchrotron-radiation-based x-ray micro-computed tomography (SRµCT) was used to investigate structural changes within the hepatic sinusoids network in the NIF mouse in comparison to patients... (More)

Metabolic dysfunction-associated steatohepatitis (MASH) is a common but frequently unrecognized complication of obesity and type 2 diabetes. The association between these conditions is multifaceted and involves complex interactions between metabolic, inflammatory, and genetic factors. Here we assess the underlying structural and molecular processes focusing on the immunological phase of MASH in the nonobese inflammation and fibrosis (NIF) mouse model and compare it to the human disease as well as other murine models. Histopathology together with synchrotron-radiation-based x-ray micro-computed tomography (SRµCT) was used to investigate structural changes within the hepatic sinusoids network in the NIF mouse in comparison to patients with different severities of MASH. A time-course, bulk RNA-sequencing analysis of liver tissue from NIF mice was performed to identify the dynamics of key processes associated with the pathogenesis. Transcriptomics profiling of the NIF mouse revealed a gradual transition from an initially reactive inflammatory response to a regenerative, pro-fibrotic inflammatory response suggesting new avenues for treatment strategies that focus on immunological targets. Despite the lack of metabolic stress induced liver phenotype, a large similarity between the NIF mouse and the immunological phase of human MASH was detected. The translational value was further supported by the comparative analyses with MASH patients and additional animal models. Finally, the impact of diets known to induce metabolic stress, was explored in the NIF mouse. An obesogenic diet was found to induce key physiological, metabolic, and histologic changes akin to those observed in human MASH.

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organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
14
issue
1
article number
23014
publisher
Nature Publishing Group
external identifiers
  • scopus:85205605422
  • pmid:39362932
ISSN
2045-2322
DOI
10.1038/s41598-024-73150-z
language
English
LU publication?
yes
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Publisher Copyright: © 2024. The Author(s).
id
99c437c9-c403-4601-a465-3094eaca266b
date added to LUP
2024-10-11 01:59:43
date last changed
2025-07-05 01:36:48
@article{99c437c9-c403-4601-a465-3094eaca266b,
  abstract     = {{<p>Metabolic dysfunction-associated steatohepatitis (MASH) is a common but frequently unrecognized complication of obesity and type 2 diabetes. The association between these conditions is multifaceted and involves complex interactions between metabolic, inflammatory, and genetic factors. Here we assess the underlying structural and molecular processes focusing on the immunological phase of MASH in the nonobese inflammation and fibrosis (NIF) mouse model and compare it to the human disease as well as other murine models. Histopathology together with synchrotron-radiation-based x-ray micro-computed tomography (SRµCT) was used to investigate structural changes within the hepatic sinusoids network in the NIF mouse in comparison to patients with different severities of MASH. A time-course, bulk RNA-sequencing analysis of liver tissue from NIF mice was performed to identify the dynamics of key processes associated with the pathogenesis. Transcriptomics profiling of the NIF mouse revealed a gradual transition from an initially reactive inflammatory response to a regenerative, pro-fibrotic inflammatory response suggesting new avenues for treatment strategies that focus on immunological targets. Despite the lack of metabolic stress induced liver phenotype, a large similarity between the NIF mouse and the immunological phase of human MASH was detected. The translational value was further supported by the comparative analyses with MASH patients and additional animal models. Finally, the impact of diets known to induce metabolic stress, was explored in the NIF mouse. An obesogenic diet was found to induce key physiological, metabolic, and histologic changes akin to those observed in human MASH.</p>}},
  author       = {{Schmidt-Christensen, Anja and Eriksson, Gustaw and Laprade, William M. and Pirzamanbein, Behnaz and Hörnberg, Maria and Linde, Kajsa and Nilsson, Julia and Skarsfeldt, Mark and Leeming, Diana J. and Mokso, Rajmund and Verezhak, Mariana and Dahl, Anders and Dahl, Vedrana and Önnerhag, Kristina and Oghazi, Massoud Rezaee and Mayans, Sofia and Holmberg, Dan}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Structure-function analysis of time-resolved immunological phases in metabolic dysfunction-associated fatty liver disease (MASH) comparing the NIF mouse model to human MASH}},
  url          = {{http://dx.doi.org/10.1038/s41598-024-73150-z}},
  doi          = {{10.1038/s41598-024-73150-z}},
  volume       = {{14}},
  year         = {{2024}},
}