<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma"^^ . "Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the sixth\r\nmost frequent cancer and represents the third cause of global cancer- related mortality [1]. The\r\nknown aetiologies of HCC could be of viral (Hepatitis B, Hepatitis C infection) and non-viral\r\n(non-alcoholic fatty liver disease (NAFLD) and alcoholic steatohepatitis (ASH)) nature,\r\nalthough NAFLD is becoming the predominant cause of chronic liver disease in western\r\ncountries. NAFLD, a condition presenting as the hepatic manifestation of the metabolic\r\nsyndrome, is favoured by diet-induced obesity and insulin resistance [2]. NAFLD is\r\ncharacterized by progressive degree of severity, inducing Non-alcoholic steatohepatitis\r\n(NASH), its most detrimental stage that precedes liver cirrhosis and HCC onset [3, 4].\r\nCurrently, no approved therapy is available for NASH, and many studies ongoing worldwide\r\nare focused in the effort to develop new treatments.\r\nIn the last two decades the essential role of bile acids in regulating metabolism has been\r\nuncovered and driven an increased amount of research to find suitable molecules for targeting\r\nthe main bile acid receptor, FXR [5]. This led to the development of several FXR agonist, many\r\nof which are currently under clinical trials testing. Among them, Tropifexor, a highly potent\r\nsynthetic agonist, demonstrated safety and tolerability during clinical trials, both alone and in\r\ncombination with other compounds, and will likely proceed to phase III testing in the near future\r\n[6, 7]. However, no research has to date evaluated the effects of sustained treatment with\r\nTropifexor nor other FXR agonist, in the context of late NASH and during NASH-to-HCC\r\ntransition. To study this question, I employed different dietary models of murine NASH and\r\ntested several FXR agonists including Tropifexor in both short-and long-term therapeutic\r\nfashion. I confirmed the extraordinary efficacy of Tropifexor in reversing NASH by driving\r\nimportant improvements in obesity, glucose and lipid metabolism, effectively reducing bile\r\nacids and leading to a clearance of hepatic steatosis in the short-term experiments, showing also\r\nrelevant modulations on lymphoid-and myeloid-induced inflammation. Nevertheless, some\r\nconcerning effects related to hepatomegaly induction stimulated by elevated hepatocyte\r\nproliferation and activation of a pro-carcinogenic signature, balanced by activation of cellular\r\nsenescence and polyploidy, sparked my interest for further investigation after prolonged\r\nadministration of Tropifexor. The long-term experiments faithfully recapitulated the efficient\r\nmetabolic improvements induced in the liver by Tropifexor, successfully reversing severe\r\nNASH and improving fibrosis, but at the expenses of increased amount of hepatic lesions.\r\nAdditional evaluation led to the identification of pronounced levels of Endoplasmic Reticulum\r\n15\r\n(ER) stress, likely caused by specific hepatic retention of hydrophobic bile acids species,\r\nfavoured especially by a low of dose of Tropifexor. In addition, a comparison of a high and low\r\ndose of Tropifexor revealed essential pharmacokinetic differences that importantly impact on\r\nthe diversity of liver damage induced and on the biliary stress stimulation driving regenerative\r\nchanges. Furthermore, long-term administration of Tropifexor presented dual effects on both\r\nlymphoid and myeloid immunity, showing contradicting effects in the inflammation\r\nmodulation. Additional studies are definitely required to dissect in detail the molecular\r\nmechanisms at the base of the observed phenotype. Yet, the present study clearly indicated that\r\na prolonged administration of Tropifexor in late NASH in proximity of HCC transition could\r\nrather synergize the signals that drive malignant transformation and increase tumour incidence\r\nin spite of NASH improvement"^^ . "2024" . . . . . . . "Enrico"^^ . "Focaccia"^^ . "Enrico Focaccia"^^ . . . . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (PDF)"^^ . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Exploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #34338 \n\nExploring the effects of different FXR agonists on progression of Non-Alcoholic Steatohepatitis and its transition to Hepatocellular Carcinoma\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .