Kostimulatorische Interaktionen bei der Entwicklung der nichtalkoholischen Steatohepatitis und Leberfibrose

• Antragsteller: Dr. Antonios Chatzigeorgiou
• Fachliche Zuordnung: Gastroenterologie ; Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin
• Förderung: Förderung von 2018 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 396067872

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

Non-alcoholic fatty liver disease (NAFLD) is a global health problem with a rapidly increasing prevalence, associated with obesity, type 2 diabetes mellitus, and aging. The disease encompasses a spectrum ranging from simple NAFLD to nonalcoholic steatohepatitis (NASH), which involves inflammation and fibrosis, potentially leading to cirrhosis and hepatocellular carcinoma. The excessive influx of fatty acids into the liver and insulin resistance in obese conditions can cause stress and injury to hepatocytes, leading to inflammation and the development of fibrosis. Immune cell infiltration and activation of Kupffer cells play a key role in the progression from NAFLD to NASH. Additionally, adaptive immune responses involving CD4+ and CD8+ cells contribute significantly to NASH development. Intercellular communication and the role of co-stimulatory molecules such as CD40 and CD40L have been implicated in regulating inflammation and cellular responses in the liver. Investigating the cellular distribution and regulation of CD40/CD40L in the liver during NASH development and studying their potential contributions can provide insights into the pathophysiology of NASH. Firstly, by using a diet-induced NASH model, we identified immune and parenchymal liver cell populations that express CD40 and CD40L. CD40/CD40L expression was analyzed in various liver cell populations, including liver endothelial cells, Kupffer cells, monocyte-derived macrophages, CD4+ T cells, CD8+ T cells, and NK cells. High expression of CD40 was found on macrophages, Kupffer cells, and endothelial cells, and its expression was significantly upregulated in diet-induced NASH. CD40L expression was observed on lymphocytes and endothelial cells and was also upregulated during NASH development. In further experiments we examined the role of CD40L on lymphocytes during NASH development utilizing lymphocyte-specific CD40L-deficient mice. In this case, by using the CD4-Cre system a ∼50% deletion in CD4+ T cells and no significant deletion in CD8+ T cells was found. The deletion of CD40L in T cells in the model of diet-induced NASH also did not result in noticeable differences in liver steatosis and fibrosis, or gene expression related to inflammation, fibrosis, and metabolism. Moreover, we performed additional experiments in the context of NAFLD/NASH pathogenesis; for instance, we investigated whether NAFLD is associated with senescence, particularly in non-aged organisms. Young mice subjected to two different diet-induced NAFLD models were found to exhibit molecular features of stressinduced senescence during NAFLD regardless of obesity.

Projektbezogene Publikationen (Auswahl)

• The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis. Hepatology, 71(1), 363-374.
  Papatheodoridi, Alkistis‐Maria; Chrysavgis, Lampros; Koutsilieris, Michael & Chatzigeorgiou, Antonios
  
• Fate of Adipose Progenitor Cells in Obesity-Related Chronic Inflammation. Frontiers in Cell and Developmental Biology, 8.
  Pyrina, Iryna; Chung, Kyoung-Jin; Michailidou, Zoi; Koutsilieris, Michael; Chavakis, Triantafyllos & Chatzigeorgiou, Antonios
  
• Metabolic inflammation as an instigator of fibrosis during non-alcoholic fatty liver disease. World Journal of Gastroenterology, 26(17), 1993-2011.
  Katsarou, Angeliki; Moustakas, Ioannis I.; Pyrina, Iryna; Lembessis, Panagiotis; Koutsilieris, Michael & Chatzigeorgiou, Antonios
  
• Hepatic Senescence Accompanies the Development of NAFLD in Non-Aged Mice Independently of Obesity. International Journal of Molecular Sciences, 22(7), 3446.
  Moustakas, Ioannis I.; Katsarou, Angeliki; Legaki, Aigli-Ioanna; Pyrina, Iryna; Ntostoglou, Konstantinos; Papatheodoridi, Alkistis-Maria; Gercken, Bettina; Pateras, Ioannis S.; Gorgoulis, Vassilis G.; Koutsilieris, Michael; Chavakis, Triantafyllos & Chatzigeorgiou, Antonios
  
• Hepatocyte Mitochondrial Dynamics and Bioenergetics in Obesity-Related Non-Alcoholic Fatty Liver Disease. Current Obesity Reports, 11(3), 126-143.
  Legaki, Aigli-Ioanna; Moustakas, Ioannis I.; Sikorska, Michalina; Papadopoulos, Grigorios; Velliou, Rallia-Iliana & Chatzigeorgiou, Antonios
  
• Analysis of the Role of Stellate Cell VCAM-1 in NASH Models in Mice. International Journal of Molecular Sciences, 24(5), 4813.
  Chung, Kyoung-Jin; Legaki, Aigli-Ioanna; Papadopoulos, Grigorios; Gercken, Bettina; Gebler, Janine; Schwabe, Robert F.; Chavakis, Triantafyllos & Chatzigeorgiou, Antonios
  
• Integrated omics analysis for characterization of the contribution of high fructose corn syrup to non-alcoholic fatty liver disease in obesity. Metabolism, 144, 155552.
  Papadopoulos, Grigorios; Legaki, Aigli-Ioanna; Georgila, Konstantina; Vorkas, Panagiotis; Giannousi, Eirini; Stamatakis, George; Moustakas, Ioannis I.; Petrocheilou, Maria; Pyrina, Iryna; Gercken, Bettina; Kassi, Eva; Chavakis, Triantafyllos; Pateras, Ioannis S.; Panayotou, George; Gika, Helen; Samiotaki, Martina; Eliopoulos, Aristides G. & Chatzigeorgiou, Antonios