%0 Generic
%A Focaccia, Enrico
%C Heidelberg
%D 2024
%F heidok:34338
%R 10.11588/heidok.00034338
%T Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma
%U https://archiv.ub.uni-heidelberg.de/volltextserver/34338/
%X Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the sixth  most frequent cancer and represents the third cause of global cancer- related mortality [1]. The  known aetiologies of HCC could be of viral (Hepatitis B, Hepatitis C infection) and non-viral  (non-alcoholic fatty liver disease (NAFLD) and alcoholic steatohepatitis (ASH)) nature,  although NAFLD is becoming the predominant cause of chronic liver disease in western  countries. NAFLD, a condition presenting as the hepatic manifestation of the metabolic  syndrome, is favoured by diet-induced obesity and insulin resistance [2]. NAFLD is  characterized by progressive degree of severity, inducing Non-alcoholic steatohepatitis  (NASH), its most detrimental stage that precedes liver cirrhosis and HCC onset [3, 4].  Currently, no approved therapy is available for NASH, and many studies ongoing worldwide  are focused in the effort to develop new treatments.  In the last two decades the essential role of bile acids in regulating metabolism has been  uncovered and driven an increased amount of research to find suitable molecules for targeting  the main bile acid receptor, FXR [5]. This led to the development of several FXR agonist, many  of which are currently under clinical trials testing. Among them, Tropifexor, a highly potent  synthetic agonist, demonstrated safety and tolerability during clinical trials, both alone and in  combination with other compounds, and will likely proceed to phase III testing in the near future  [6, 7]. However, no research has to date evaluated the effects of sustained treatment with  Tropifexor nor other FXR agonist, in the context of late NASH and during NASH-to-HCC  transition. To study this question, I employed different dietary models of murine NASH and  tested several FXR agonists including Tropifexor in both short-and long-term therapeutic  fashion. I confirmed the extraordinary efficacy of Tropifexor in reversing NASH by driving  important improvements in obesity, glucose and lipid metabolism, effectively reducing bile  acids and leading to a clearance of hepatic steatosis in the short-term experiments, showing also  relevant modulations on lymphoid-and myeloid-induced inflammation. Nevertheless, some  concerning effects related to hepatomegaly induction stimulated by elevated hepatocyte  proliferation and activation of a pro-carcinogenic signature, balanced by activation of cellular  senescence and polyploidy, sparked my interest for further investigation after prolonged  administration of Tropifexor. The long-term experiments faithfully recapitulated the efficient  metabolic improvements induced in the liver by Tropifexor, successfully reversing severe  NASH and improving fibrosis, but at the expenses of increased amount of hepatic lesions.  Additional evaluation led to the identification of pronounced levels of Endoplasmic Reticulum  15  (ER) stress, likely caused by specific hepatic retention of hydrophobic bile acids species,  favoured especially by a low of dose of Tropifexor. In addition, a comparison of a high and low  dose of Tropifexor revealed essential pharmacokinetic differences that importantly impact on  the diversity of liver damage induced and on the biliary stress stimulation driving regenerative  changes. Furthermore, long-term administration of Tropifexor presented dual effects on both  lymphoid and myeloid immunity, showing contradicting effects in the inflammation  modulation. Additional studies are definitely required to dissect in detail the molecular  mechanisms at the base of the observed phenotype. Yet, the present study clearly indicated that  a prolonged administration of Tropifexor in late NASH in proximity of HCC transition could  rather synergize the signals that drive malignant transformation and increase tumour incidence  in spite of NASH improvement