Unraveling MASLD: Insights from Ex vivo Models

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver condition globally, affecting over 30% of the adult population. Characterized by abnormal fat accumulation in the liver, MASLD is often linked to metabolic syndrome and can progress to a more severe form, metabolic dysfunction-associated steatohepatitis (MASH), which is marked by inflammation, fibrosis, and potential adverse outcomes. Current treatment approaches primarily focus on lifestyle modifications, although the recent FDA approval of resmetirom represents a significant advancement in treating MASH patients with moderate to severe fibrosis. This thesis explores the development and progression of MASLD using precision-cut liver slices (PCLS) from both human and mouse. PCLS offer an advanced ex vivo model that retains the liver's complex structure and cellular interactions, making them invaluable for studying liver diseases. The research extends traditional short-term PCLS models by examining human liver slices under prolonged incubation with a highly nutrient-rich medium to emulate MASLD's clinical trajectory, including steatosis, MASH, and fibrosis. Additionally, the impact of pro-inflammatory agents such as lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF-α) on liver slices were studied, revealing their roles in inflammation and fibrosis. Comparative transcriptomic analysis between human and mouse PCLS incubated under similar conditions highlights species-specific metabolic responses, emphasizing the relevance of human PCLS in MASLD research. This work provides new insights into the mechanisms of MASLD and offers innovative methodologies for drug screening and disease investigation.