Novel molecular targets in hepatic stellate cells for the treatment of liver fibrosis
|PhD ceremony:||Ms N.F. (Natalia) Oyarce Diaz-Smith Cortínez|
|When:||July 07, 2020|
|Supervisors:||prof. dr. K.N. (Klaas Nico) Faber, prof. dr. A.J. (Han) Moshage|
|Where:||Academy building RUG|
|Faculty:||Medical Sciences / UMCG|
Short English AbstractLiver fibrosis is the result of chronic liver diseases that lead to cell death and scarring due to extracellular matrix (ECM) deposition. Hepatic stellate cells (HSC) are myofibroblast-like cells that activate upon injury and produce ECM. HSC activation, from quiescent HSC (qHSC) to activated HSC (aHSC) is controlled by the pro-fibrogenic cytokine transforming growth factor-beta (TGFβ) and regulates the production of alpha-smooth muscle actin (αSMA) and collagen-I, key markers of aHSC. aHSC contribute to the progression of liver fibrosis, so finding novel drugs that prevent or reverse the activation of HSC is an important step in developing effective treatments for liver fibrosis. We investigated the contribution of mitochondrial metabolism towards HSC activation and in Chapter 2 and Chapter 3, we targeted metabolic pathways that are involved in HSC activation. Excessive ECM deposition is the process that ultimately causes the scarring of the liver causing cirrhosis. Thus, we studied the molecular mechanisms driving collagen-I export in Chapter 4 and Chapter 5, targeted key proteins in this pathway to find novel targets to treat liver fibrosis. Results from these studies show that specific inhibitors of mitochondrial metabolism and/or ECM production, several already being evaluated in clinical trials for other diseases, show great potential for the future treatment of liver fibrosis.