“The functional involvement of YAP and the interaction with ER-stress during hepatic stellate cell activation in liver fibrosis”

Student thesis: Master's Thesis

Abstract

Upon perpetual liver damage, the hepatic stellate cells (HSCs) become activated and are the main contributors to an excessive deposition of extracellular matrix (ECM) proteins, causing scarring of the liver tissue or liver fibrosis. Although a lot of research about the mechanisms leading to HSC activation has been done, this process is not entirely understood.
The Hippo pathway and its core mediator YAP have been shown to play a major role during liver fibrosis. The activation of YAP and its translocation towards the nucleus can drive HSC activation in vitro and fibrogenesis in vivo. Until now, it remains unknown how YAP is regulated. In literature, it has been shown that the Hippo pathway in other primary cell types and cancer cell lines can interact with other pathways involved in liver fibrosis, such as ER-stress. With our research, we aimed to investigate the role of ER-stress and its interaction with the Hippo signalling during HSC activation and made use of three different cell systems: a human HSC cell line (LX-2 cells), 2D/3D cultured primary mouse HSCs and in vivo activated primary mouse HSCs.
Although ER-stress is an early event during primary HSC activation, this was not confirmed in in vivo activated HSCs. These in vivo activated cells showed a strong upregulation of HSC activation markers and YAP downstream target genes. On the other hand, chemically induced ER-stress through tunicamycin (TM) treatment leads to the upregulation of the unfolded protein response, followed by the induction of HSC activation and downregulation of the YAP downstream target Ankrd1 in LX-2 cells. This TM-induced ER-stress was insufficient to drive the activation of 3D cultured quiescent primary HSCs.
Together, these data suggest that a possible interaction between the Hippo signalling and ER-stress exists, although it is not entirely clear how this is regulated. Further experiments should clarify how this process is orchestrated.
Date of AwardJun 2017
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
SupervisorInge Mannaerts (Co-promotor)

Keywords

  • BMW
  • 2de master
  • Hippo

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