Structure-function analysis of time-resolved immunological phases in metabolic dysfunction-associated fatty liver...

Area of Science:

• Hepatology and Immunology
• Molecular Biology
• Medical Imaging

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a growing health concern linked to obesity and type 2 diabetes.
• Understanding the immunological underpinnings of MASH is crucial for developing effective treatments.
• Existing animal models may not fully recapitulate the human disease's complexity.

Purpose of the Study:

• To investigate the immunological phase of MASH using a nonobese inflammation and fibrosis (NIF) mouse model.
• To compare the NIF mouse model's hepatic changes with human MASH patients and other animal models.
• To identify molecular and structural changes associated with MASH pathogenesis.

Main Methods:

• Histopathology and synchrotron-radiation-based x-ray micro-computed tomography (SRµCT) for structural analysis of liver sinusoids.
• Time-course bulk RNA-sequencing to analyze gene expression dynamics in NIF mice.
• Comparative analysis of NIF mice, human MASH patients, and other murine models.

Main Results:

• The NIF mouse model exhibited a transition from reactive to pro-fibrotic inflammation, mirroring human MASH immunology.
• SRµCT revealed structural similarities in hepatic sinusoids between NIF mice and human MASH patients.
• Transcriptomic profiling identified key molecular pathways driving MASH pathogenesis in the NIF model.
• An obesogenic diet induced MASH-like physiological, metabolic, and histologic changes in NIF mice.

Conclusions:

• The NIF mouse model effectively mimics the immunological aspects of human MASH, despite lacking overt metabolic stress.
• This model provides valuable insights into MASH pathogenesis and supports immunological targets for therapy.
• Dietary interventions can modulate MASH-like phenotypes in susceptible individuals, highlighting a potential therapeutic avenue.