Exploring the effects of different bile acids receptor agonists in Non-Alcoholic Steatohepatitis (NASH) and NASH-related hepatocarcinogenesis

Non-Alcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and presents as a condition with progressive severity. Non-Alcoholic Steatohepatitis (NASH) consists in its most detrimental stage, preceding liver cirrhosis, and is an independent risk factor for developing Hepatocellular Carcinoma (HCC), the most common primary liver cancer. NASH currently lacks approved treatments and further studies to develop new therapeutic strategies are urgently required. Several studies highlighted the importance of the bile acid receptor FXR in regulating glucose and lipid metabolism, making it an appealing target in the context of obesity, NASH and cholestatic disease. Currently, several FXR agonists are being tested in clinical trials for NASH. However, the efficacy of the compounds available at the moment seems to have a large spectrum of outcomes, and we were interested in identifying the best candidate and defining the features of its action. By employing dietary models of NASH in rodents, we tested different FXR agonists in preventive and therapeutic ways. The animal experiments were carried out in parallel with mainly histological analysis, classical molecular biology assays, flow cytometric measures and major Omics analysis performed on the tissue collected. Our results show that only one of the compounds tested was really able to effectively reverse the major features of NASH and metabolic syndrome, in particular steatosis and inflammation. However, some key findings revealed the activation of pro-carcinogenic pathways, which could potentially expose the liver to an additional load of signals that drive malignant transformation.