OpenTox Euro 2019 talk: Investigating the link between cholestasis and fibrosis

Disrupted regulation and accumulation of bile salts (BS) in the liver can contribute towards progressive liver damage, cholestasis and fibrosis. Adverse outcome pathways (AOPs) are a promising tool for the development of in vitro toxicity screening tests as they provide us with key events, which we can use when establishing cell-based models. The proposed AOP for cholestasis and established AOP for liver fibrosis provide us with specific events involved in each condition.  However, certain key events occur in both AOPs such as apoptosis and inflammation. Here, we investigated the role of BS in the progression of cholestatic injury and liver fibrosis using 3D scaffold-free multicellular human liver microtissues (MTs) comprising the cell lines HepaRG, THP-1 and hTERT-HSCs. We demonstrated that low concentrations of BS led to down-regulation of CYP7A1 and increased stellate cell activation, which are key events specific to cholestasis and fibrosis, respectively. We also identified that BS elicit apoptosis/cell death and inflammation both of which are common to both AOPs. In conclusion, by utilising this in vitro system and AOPs we have identified that BS accumulation contributes towards not only cholestatic injury but there is a link between cholestasis and liver fibrosis.