Studies on the role of adrenergic antagonists in the treatment of metabolic-dysfunction associated fatty liver disease and liver fibrosis

Metabolic dysfunction associated fatty liver disease (MAFLD) is a condition characterized by steatosis, the accumulation of fat in the liver in the absence of alcohol consumption. Nowadays, MAFLD is the most common form of chronic liver disease worldwide. MAFLD can progress from simple steatosis to Non-Alcoholic Steatohepatitis (NASH) as a consequence of the exposure of the liver to excessive amounts of (toxic) lipids, in particular free fatty acids. The term lipotoxicity is used to describe the deleterious effects of lipid exposure to cells. In particular hepatocytes are susceptible to lipotoxicity. The exposure of hepatocytes to toxic lipids leads to hepatocyte damage and death and chronic inflammation. The chronic inflammatory stage of MAFLD is termed NASH. The exposure of hepatocytes to toxic lipids leads to increased generation of reactive oxygen species (ROS) and organellar dysfunction. The generation of ROS and hepatocyte damage and death also lead to the activation of non-parenchymal cells in the liver, in particular Kupffer cells, the resident macrophages of the liver, and hepatic stellate cells, the vitamin-A storing cells of the liver. Activation of stellate cells leads to excessive proliferation and synthesis of extracellular matrix components, resulting in fibrosis and cirrhosis. Cirrhosis is the irreversible end stage of liver disease and can ultimately lead to liver failure and death.
Adrenergic signalling may be involved in the development and progression of MAFLD to NASH and cirrhosis, therefore, the AIM of this thesis was to investigate whether beta- and alpha-adrenergic blockers (doxazosin (DX) and carvedilol (CV)) can attenuate lipotoxicity in hepatocytes and reverse, prevent or stop stellate cell activation and fibrogenesis.