PhD defence K. (Ke) Luo

Investigating disease models and antifibrotic therapies ex vivo: a focus on liver fibrosis and metabolic dysfunction-associated steatohepatitis

The thesis focuses on investigating antifibrotic therapies for liver fibrosis and ex vivo models of Metabolic Dysfunction-Associated Steatohepatitis (MASH) using precision-cut liver slices (PCLS). In the first part, the antifibrotic potential of natural compounds such as naringenin, asiatic acid, and icariin is evaluated using PCLS prepared from mice and both healthy and cirrhotic human livers. Additionally, the prostaglandin E2-EP4 receptor agonist rivenprost is examined for its promising effects in reducing fibrogenesis using PCLS from rats fed a high-fat, high-cholesterol (HFHC) diet, as well as PCLS from human liver. 

In the second part, an ex vivo MASH model is developed to mimic metabolic and inflammatory characteristics. Human PCLS are exposed to sugars, fatty acids, insulin (GFIPO), and inflammatory stimuli like lipopolysaccharide (LPS) and TNF-α to replicate MASH's metabolic and inflammatory components. Human PCLS are exposed to factors such as lipopolysaccharide (LPS) and Tumor necrosis factor-alpha (TNF-α) to replicate inflammation and fibrosis. Furthermore, we isolated and characterized extracellular vesicles (EVs) from PCLS derived from both healthy and MASH cirrhotic livers that were cultured in either a normal or GFIPO medium. These EVs are further investigated as messengers mediating disease progression and as potential biomarkers for MASH.