NAFLD-NASH-HCC progression: mechanisms of stage-transitions and identification of time windows for prevention

• Applicant: Professor Dr. Ahmed Ghallab
• Subject Area: Gastroenterology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457840828

• Final Report Year: 2024

Final Report Abstract

Metabolic dysfunction associated fatty liver disease (MAFLD) is the most common chronic liver disease in Western countries, which may progress to steatohepatitis (MASH) and eventually to cirrhosis and hepatocellular carcinoma (HCC). Because of poor understanding of the driving molecular mechanisms the current therapeutic options are limited. In this project we have established a mouse model that recapitulates MAFLD progression as in human patients. Key results include: (1) identification of the key events in MAFLD progression; (2) discovery of “Zombie cells” as drivers of tissue inflammation and carcinogenesis; (3) Impaired glyoxylate detoxification in MAFLD as a risk factor for hyperoxaluria; (4) Identification of macropinocytosis as a key event in MAFLD progression and therapeutic interventions; (5) Inhibition of the renal ASBT as a possible therapeutic target in cholemic nephropathy; and (6) targeting ductular reaction prevents disease progression. Translation relevance of these findings was tested in blood as well as tissue samples of patients with MAFLD.

Publications

• Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria. Cell Reports, 36(8), 109526.
  Gianmoena, Kathrin; Gasparoni, Nina; Jashari, Adelina; Gabrys, Philipp; Grgas, Katharina; Ghallab, Ahmed; Nordström, Karl; Gasparoni, Gilles; Reinders, Jörg; Edlund, Karolina; Godoy, Patricio; Schriewer, Alexander; Hayen, Heiko; Hudert, Christian A.; Damm, Georg; Seehofer, Daniel; Weiss, Thomas S.; Boor, Peter; Anders, Hans-Joachim ... & Cadenas, Cristina
  
• Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression. Cells, 10(10), 2516.
  Ghallab, Ahmed; Myllys, Maiju; Friebel, Adrian; Duda, Julia; Edlund, Karolina; Halilbasic, Emina; Vucur, Mihael; Hobloss, Zaynab; Brackhagen, Lisa; Begher-Tibbe, Brigitte; Hassan, Reham; Burke, Michael; Genc, Erhan; Frohwein, Lynn Johann; Hofmann, Ute; Holland, Christian H.; González, Daniela; Keller, Magdalena; Seddek, Abdel-latif ... & Hengstler, Jan G.
  
• In vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assay. Toxicology Letters, 368, 33-46.
  Brecklinghaus, Tim; Albrecht, Wiebke; Duda, Julia; Kappenberg, Franziska; Gründler, Lisa; Edlund, Karolina; Marchan, Rosemarie; Ghallab, Ahmed; Cadenas, Cristina; Rieck, Adrian; Vartak, Nachiket; Tolosa, Laia; Castell, José V.; Gardner, Iain; Halilbasic, Emina; Trauner, Michael; Ullrich, Anett; Zeigerer, Anja; Demirci, Turgunbayer Özlem ... & Hengstler, Jan G.
  
• Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity. Journal of Hepatology, 77(1), 71-83.
  Ghallab, Ahmed; Hassan, Reham; Hofmann, Ute; Friebel, Adrian; Hobloss, Zaynab; Brackhagen, Lisa; Begher-Tibbe, Brigitte; Myllys, Maiju; Reinders, Joerg; Overbeck, Nina; Sezgin, Selahaddin; Zühlke, Sebastian; Seddek, Abdel-latif; Murad, Walaa; Brecklinghaus, Tim; Kappenberg, Franziska; Rahnenführer, Jörg; González, Daniela; Goldring, Christopher ... & Hengstler, Jan G.
  
• Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury. eLife, 11.
  Wehling, Lilija; Keegan, Liam; Fernández-Palanca, Paula; Hassan, Reham; Ghallab, Ahmed; Schmitt, Jennifer; Tang, Yingyue; Le Marois, Maxime; Roessler, Stephanie; Schirmacher, Peter; Kummer, Ursula; Hengstler, Jan G.; Sahle, Sven & Breuhahn, Kai
  
• Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet. Cells, 12(18), 2331.
  Custodio, Raly James Perez; Hobloss, Zaynab; Myllys, Maiju; Hassan, Reham; González, Daniela; Reinders, Jörg; Bornhorst, Julia; Weishaupt, Ann-Kathrin; Seddek, Abdel-latif; Abbas, Tahany; Friebel, Adrian; Hoehme, Stefan; Getzmann, Stephan; Hengstler, Jan G.; van Thriel, Christoph & Ghallab, Ahmed
  
• In vitro to in vivo acetaminophen hepatotoxicity extrapolation using classical schemes, pharmacodynamic models and a multiscale spatial-temporal liver twin. Frontiers in Bioengineering and Biotechnology, 11.
  Dichamp, Jules; Cellière, Geraldine; Ghallab, Ahmed; Hassan, Reham; Boissier, Noemie; Hofmann, Ute; Reinders, Joerg; Sezgin, Selahaddin; Zühlke, Sebastian; Hengstler, Jan G. & Drasdo, Dirk
  
• Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice. Frontiers in Pharmacology, 14.
  Fendt, Rebekka; Ghallab, Ahmed; Myllys, Maiju; Hofmann, Ute; Hassan, Reham; Hobloss, Zaynab; González, Daniela; Brackhagen, Lisa; Marchan, Rosemarie; Edlund, Karolina; Seddek, Abdel-Latif; Abdelmageed, Noha; Blank, Lars M.; Schlender, Jan-Frederik; Holland, Christian H.; Hengstler, Jan G. & Kuepfer, Lars
  
• Sublethal necroptosis signaling promotes inflammation and liver cancer. Immunity, 56(7), 1578-1595.e8.
  Vucur, Mihael; Ghallab, Ahmed; Schneider, Anne T.; Adili, Arlind; Cheng, Mingbo; Castoldi, Mirco; Singer, Michael T.; Büttner, Veronika; Keysberg, Leonie S.; Küsgens, Lena; Kohlhepp, Marlene; Görg, Boris; Gallage, Suchira; Barragan, Avila Jose Efren; Unger, Kristian; Kordes, Claus; Leblond, Anne-Laure; Albrecht, Wiebke; Loosen, Sven H. ... & Luedde, Tom
  
• A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage. iScience, 27(2), 108077.
  Zhao, Jieling; Ghallab, Ahmed; Hassan, Reham; Dooley, Steven; Hengstler, Jan Georg & Drasdo, Dirk
  
• Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease. Molecular Systems Biology, 20(3), 187-216.
  Burbano de Lara, Sebastian; Kemmer, Svenja; Biermayer, Ina; Feiler, Svenja; Vlasov, Artyom; D.’Alessandro, Lorenza A.; Helm, Barbara; Mölders, Christina; Dieter, Yannik; Ghallab, Ahmed; Hengstler, Jan G.; Körner, Christiane; Matz-Soja, Madlen; Götz, Christina; Damm, Georg; Hoffmann, Katrin; Seehofer, Daniel; Berg, Thomas; Schilling, Marcel ... & Klingmüller, Ursula
  
• Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury. Springer Science and Business Media LLC.
  Vartak, Nachiket; Damle-Vartak, Amruta; Joers, Simone; Guenther, Georgia; Lam, Macrina; Sator-Schmitt, Melanie; Poth, Tanja; Hofmann, Ute; Kovacevic, Jasna; Ringelhan, Marc; Ghallab, Ahmed; Dürl, Stephanie; Schmid, Roland; Angel, Peter; Hengstler, Jan & Geisler, Fabian
  
• Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis. Journal of Hepatology, 80(2), 268-281.
  Ghallab, Ahmed; González, Daniela; Strängberg, Ellen; Hofmann, Ute; Myllys, Maiju; Hassan, Reham; Hobloss, Zaynab; Brackhagen, Lisa; Begher-Tibbe, Brigitte; Duda, Julia C.; Drenda, Carolin; Kappenberg, Franziska; Reinders, Joerg; Friebel, Adrian; Vucur, Mihael; Turajski, Monika; Seddek, Abdel-latief; Abbas, Tahany; Abdelmageed, Noha ... & Hengstler, Jan G.