Functional imaging to explore a so far unconsidered mechanism of acetaminophen hepatotoxicity

• Applicant: Dr. Ahmed Ghallab
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517010379

Intoxication with paracetamol (APAP) is frequent and represents the second most common cause of liver transplantation worldwide. In our previous work, we identified a so far unrecognized phenomenon during APAP induced liver damage. Two to six hours after administration of hepatotoxic doses of APAP to mice, a transient cholestatic phase is observed with increased bile acid concentrations in blood and liver tissue. Intravital two-photon imaging demonstrated that bile canaliculi form protrusions into hepatocytes. Afterwards, enrichment of bile acids is observed in the cytoplasm of hepatocytes, which leads to cell death. Importantly, Myrcludex B, which blocks bile acid uptake into hepatocytes, ameliorates the transient intracellular cholestasis and strongly reduces APAP induced liver damage. Based on these preliminary results, we will systematically study how the transient cholestatic phase after APAP intoxication contributes to hepatotoxicity and if its pharmaceutical antagonization protects from liver damage. To reach this goal the following specific questions will be addressed in this project: WP1: At which position of the biliary transport chain does APAP induce cholestasis? WP2: Are endogenous bile acids increased in liver lobules and do they show a zonated enrichment pattern? WP3: Does APAP induce intrahepatic recycling of bile acids and can this be ameliorated by specific drugs? WP4: Are the observations made in mice of translational relevance?

• DFG Programme: Research Grants