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

Autor: Schmidt-Christensen A; Lund University Diabetes Center, Lund University, Lund, Sweden., Eriksson G; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Laprade WM; Technical University of Denmark, DTU, Copenhagen, Denmark., Pirzamanbein B; Technical University of Denmark, DTU, Copenhagen, Denmark.; Statistics department, Lund University, Lund, Sweden., Hörnberg M; Inficure Bio AB, Umeå, Sweden., Linde K; Inficure Bio AB, Umeå, Sweden., Nilsson J; Lund University Diabetes Center, Lund University, Lund, Sweden.; Inficure Bio AB, Umeå, Sweden., Skarsfeldt M; Nordic Bioscience A/S, Herlev, Denmark., Leeming DJ; Nordic Bioscience A/S, Herlev, Denmark., Mokso R; MAXIV laboratory, Lund University, Lund, Sweden., Verezhak M; Paul Scherrer Institut, Villigen, Switzerland., Dahl A; Technical University of Denmark, DTU, Copenhagen, Denmark., Dahl V; Technical University of Denmark, DTU, Copenhagen, Denmark., Önnerhag K; Skåne hospital, Malmö, Sweden., Oghazi MR; Connected Pathology, Lier, Belgium., Mayans S; Inficure Bio AB, Umeå, Sweden., Holmberg D; Lund University Diabetes Center, Lund University, Lund, Sweden. Dan.holmberg@umu.se.; Inficure Bio AB, Umeå, Sweden. Dan.holmberg@umu.se.; Department of Medical Biosciences, Umeå University, Umeå, Sweden. Dan.holmberg@umu.se.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 03; Vol. 14 (1), pp. 23014. Date of Electronic Publication: 2024 Oct 03.
DOI: 10.1038/s41598-024-73150-z
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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