PhD defence L.R. (Lianne) de Haan

Below is a brief summary of the dissertation:

Partial hepatectomy (PHx) is the only curative treatment option for patients with perihilar cholangiocarcinoma, a tumor that arises from the bile ducts and causes obstructive cholestasis. Tumor-induced cholestasis leads to a diminished regenerative capacity of the liver, which may complicate the post-operative clinical course. Despite surgical interventions such as preoperative biliary drainage, 90-day mortality rates of up to 18% have been reported for patients with perihilar cholangiocarcinoma that underwent PHx. Thus, there is an increasing need to pharmacologically target liver regeneration in order to overcome the diminished regenerative capacity in these patients. 

This thesis discusses the different effects of bile acids in liver regeneration. Bile acid homeostasis after PHx and the molecular pathways that target the termination phase of liver regeneration were reviewed. Also, we demonstrated that changes in gene expression induced by obstructive cholestasis are largely but not fully reversed after preoperative biliary drainage. Insight into the pathways that steer liver regeneration paves the way for pharmacological interventions, and includes the proliferative bile acid receptor farnesoid X receptor (FXR). In two studies, we demonstrated that the FXR agonist obeticholic acid unexpectedly did not induce liver regeneration after PHx in rats. The results of this study might not be fully translatable to the human situation as we demonstrated that hamsters better resemble the pathophysiology of obstructive cholestasis in humans compared to other rodents commonly used in PHx models. This thesis also includes two papers describing the use of dichlorofluorescein for the use of measuring oxidative stress in hepatocytes, which could be induced by bile acids and which serves as a trigger for liver regeneration.