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

• Published in: Scientific reports Vol. 14; no. 1; pp. 23014 - 15
• Main Authors: Schmidt-Christensen, Anja, Eriksson, Gustaw, Laprade, William M., Pirzamanbein, Behnaz, Hörnberg, Maria, Linde, Kajsa, Nilsson, Julia, Skarsfeldt, Mark, Leeming, Diana J., Mokso, Rajmund, Verezhak, Mariana, Dahl, Anders, Dahl, Vedrana, Önnerhag, Kristina, Oghazi, Massoud Rezaee, Mayans, Sofia, Holmberg, Dan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-10-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 692/699; 692/699/1503; 692/699/249; 692/699/2743; 692/699/317; Animal models; Animals; Basic Medicine; Comparative analysis; Computed tomography; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diet; Disease Models, Animal; Farmakologi och toxikologi; Fatty liver; Fatty Liver - metabolism; Fatty Liver - pathology; Fibrosis; Genetic factors; Histopathology; Humanities and Social Sciences; Humans; Immunology; Inflammation; Inflammation - metabolism; Inflammation - pathology; Liver - metabolism; Liver - pathology; Liver diseases; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity - metabolism; Obesity - pathology; Pharmacology and Toxicology; Phenotypes; Science; Science (multidisciplinary); Sequence analysis; Structure-function relationships; Transcriptomics; X-Ray Microtomography; X-rays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-73150-z

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.