Abstract 4366553: Temporal response to treatment of CL-HFS diet in respect to MASH liver development

Abstract

Introduction: Liver dysfunction contributes to cardiovascular disease (CVD) and metabolic dysfunction-associated steatohepatitis (MASH), characterized by fat accumulation, inflammation, and fibrosis. MASH co-occurs with obesity and diabetes, increasing mortality and CVD risk. As the final reversible stage before cirrhosis, MASH lacks effective treatments. Temporal dynamics and cell-cell crosstalk mechanisms remain unclear. Methods: We used a mouse MASH model induced by a choline-low, high-fat, high-sucrose diet, collecting liver tissues at weeks 1, 4, 8, and 12. Histologic, immunologic, physiologic, and single-cell transcriptomic analyses tracked disease progression. Custom quantification tools detected chronic-phase changes. Results: Progressive liver pathology developed in MASH-fed mice. Week 4 showed liver dysfunction and hepatomegaly; week 8 revealed steatosis and fibrosis, mirroring human MASH. Single-cell transcriptomics revealed hepatic and immune compartments remodeling. Kupffer cells recruited monocytes maturing into macrophages by week 1. T cell infiltration peaked at weeks 8-12. Hepatocyte stress and fibrotic signaling began at week 8. Trajectory analysis and MacSpectrum showed both monocytes and Kupffer cells contributed to inflammatory macrophages. By week 8, both expanded and expressed pro-inflammatory, fibrogenic genes. Cell-cell interactions intensified weeks 8–12, with greater immune signaling diversity and strength. Macrophages became key signal recipients, integrating an expanding ligand repertoire. Hepatocytes signaled immune cells by week 1 and assumed a coordinating role by week 8. Lgals9, Tgfb1, and Thbs1 showed temporal activation, shifting from immune-restricted to broader hepatocyte/myeloid targets. These interactions paralleled fibrosis and revealed a temporally orchestrating signaling network. Conclusion: Temporal transcriptomic and physiologic profiling reveals dynamic liver cell shifts with early myeloid infiltration and evolving immune-parenchymal interactions. The weeks 8–12 transition aligns with metabolic stress, immune dysregulation, and fibrosis. As a CVD risk factor, MASH involves chronic inflammation and macrophage reprogramming—offering insight into systemic disease.