The role of stress pathways during hepatic stellate cell activation.

Liver fibrosis is characterized by chronic injury caused by a wide array of insults such as viruses, toxins, diabetes and alcohol abuse. Upon liver injury, lipocytic quiescent hepatic stellate cells (HSCs) activate towards contractile, proliferative myofibroblast-like cells. These activated HSCs show a decreased content of the characteristic lipid droplets and produce matrix proteins leading to scar formation and liver fibrosis. Unravelling the underlying mechanisms of this HSC activation process is therefore essential to develop novel liver fibrosis treatments. In this thesis, we focused on the role of stress pathways, more specifically autophagy and the unfolded protein response, during HSC activation. We demonstrated an increased autophagic flux during the activation process and showed that inhibition of autophagy hinders HSC activation. Moreover LC3B, an autophagy related protein, colocalizes with lipid droplets in quiescent HSCs after PDGF-BB stimulation suggesting a role for autophagy during lipid droplet metabolism. During both in vitro and in vivo HSC activation we observed a strong up-regulation of unfolded protein response markers already after several hours. This early UPR seems to be JNK1- dependent and contributes to HSC activation, but does not drive the activation process. In conclusion, we identified autophagy as a novel process important for HSC activation and a possible target for the development of new anti-fibrotic therapies. The unfolded protein response on the other hand is associated with HSC activation but is not necessary to drive this process.