| Abstract: | Nonalcoholic fatty liver disease (NAFLD) is a rising cause of chronic liver disease worldwide. Although majority of patients with NAFLD are benign and non-progressive, having only steatosis, some fraction of patients develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, hepatocellular carcinoma, and eventually increased liver-related mortality. Among histological features of NAFLD, it has been reported that liver fibrosis is the most important predictor of long-term outcomes. Liver fibrosis is a dynamic process characterized by the over-accumulation of extracellular matrix due to chronic liver injury resulting from any etiology including not only NASH, but also viral infection and alcoholic liver disease. Activation of hepatic stellate cells (HSCs) has been well established as a central driver of fibrosis in experimental animal models and human liver injury. It is a transdifferentiation of quiescent, vitamin-A‑storing cells into proliferative and fibrogenic myofibroblasts. However, the discovery of novel pathways and mediators reveals the complexity of HSC activation. These emerging pathways include hedgehog, autophagy, free cholesterol, YAP1, hepcidin, and nuclear/G-protein coupled receptor-mediated signals. In addition, pathways of HSC clearance have been uncovered such as apoptosis, senescence, and reversion to an inactivated state. Thus, clarifying the underlying mechanisms of HSC activation could lead to the identification of novel therapeutic targets for NASH, and several drug candidates are currently being developed in clinical trials. |
