The role of the gaseous signaling molecule hydrogen sulfide in chronic liver disease: Special emphasis on non-alcoholic fatty liver disease

Due to the high world-wide prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become one of the major chronic liver diseases in the world. NAFLD covers a range of disease stages and in its chronic stages is always accompanied by co-morbidities, such as obesity, insulin resistance (IR), metabolic syndrome and type 2 diabetes (T2D). NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and subsequently cirrhosis and hepatocellular carcinoma (HCC). Many drugs have been proposed to treat NAFLD, however, none of them showed high efficacy, leaving a change of lifestyle in the early phase or liver transplantation at the late stages as the only effective options to treat of NAFLD. It is vital to understand the complexity of the disease and to consider the underlying mechanisms in each stage. In the current thesis we used primary rat hepatocytes and hepatic stellate cells (HSCs) to study the role of hydrogen sulfide (H2S) in NAFLD. In addition, we used a large cohort (PREVEND database, n=5562) to validate our experimental findings in a more clinical setting. We used primary rat hepatocytes to study simple steatosis and primary rat stellate cells to investigate fibrosis. In these experimental models, we investigated the role of hydrogen sulfide as well as the natural coumarin derivative esculetin. Free thiols (R-SH) were measured in serum samples of a large cohort to investigate the relation between clinical NAFLD and thiol status.