Role of Atg7 in Liver Damage and Regeneration

• Applicant: Privatdozentin Dr. Laura Elisa Buitrago Molina
• Subject Area: Gastroenterology ; Cell Biology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262580368

• Final Report Year: 2022

Final Report Abstract

In this study, we report the importance of autophagy for hepatocellular regeneration in a model of Atg7 deficiency using the liver-specific albumin promotor. In Atg7-deficient mice, we show that the extent of some liver injury abnormalities intensified with age, e.g. hepatocyte size, proliferation and fibrosis, while other pathological and biochemical parameters did not change. We demonstrated that Atg7 deficiency leaded to a hyperproliferation in a pre-stimulus state. However, the most striking effects were observed in liver regeneration and repopulation after two thirds partial hepatectomy (PHx) and cellular transplantation. Impaired liver regeneration was most prominent seen in the poor survival rate of Atg7-deficient mice accompanied by impaired lipid droplet formation that might be causative. Nonetheless, the survivors had better transaminases, decreased proliferation, and reversal of transient cellular hypertrophy with a low hepatic triglyceride content. Surprisingly, poor survival could be fully recovered by pharmacological mTOR inhibition. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation before and after PHx in plasma. In addition, we observed that Atg7 hepatodeficiency deregulates the develop of hepatocellular carcinoma in a hepatic injury model. In conclusion, we demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.

Publications

• Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. J Autoimmun, 2019. 103: p. 102289
  M. Tenspolde, K. Zimmermann, L. C. Weber, M. Hapke, M. Lieber, J. Dywicki, A. Frenzel, M. Hust, M. Galla, L. E. Buitrago-Molina, M. P. Manns, E. Jaeckel, and M. Hardtke-Wolenski
  
• Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury. Liver Int, 2020
  D. Romermann, N. Ansari, A. R. Schultz-Moreira, A. Michael, S. Marhenke, M. Hardtke- Wolenski, T. Longerich, M. P. Manns, H. Wedemeyer, A. Vogel, and L. E. Buitrago-Molina
  
• Autoimmune hepatitis induction can occur in the liver. Liver Int, 2020. 40(2): p. 377-381
  J. Dywicki, L. E. Buitrago-Molina, J. Pietrek, M. Lieber, R. Broering, T. Khera, J. Schlue, M. P. Manns, H. Wedemeyer, E. Jaeckel, and M. Hardtke-Wolenski
  
• Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun, 2020. 117: p. 102591
  L. E. Buitrago-Molina, J. Pietrek, F. Noyan, J. Schlue, M. P. Manns, H. Wedemeyer, M. Hardtke- Wolenski, and E. Jaeckel
  
• Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration. Cells, 2021. 10(6)
  L. E. Buitrago-Molina, J. Dywicki, F. Noyan, L. Schepergerdes, J. Pietrek, M. Lieber, J. Schlue, M. P. Manns, H. Wedemeyer, E. Jaeckel, and M. Hardtke-Wolenski
  
• p53-independent induction of p21 fails to control regeneration and hepatocarcinogenesis in a murine liver injury model. Cell Mol Gastroenterol Hepatol, 2021
  L. E. Buitrago-Molina, S. Marhenke, D. Becker, R. Geffers, T. Itzel, A. Teufel, H. Jaeschke, A. Lechel, K. Unger, J. Markovic, A. D. Sharma, J. U. Marquardt, M. Saborowski, A. Saborowski, and A. Vogel
  
• Splenectomy Prior to Experimental Induction of Autoimmune Hepatitis Promotes More Severe Hepatic Inflammation, Production of IL-17 and Apoptosis. Biomedicines, 2021. 9(1)
  L. E. Buitrago-Molina, J. Dywicki, F. Noyan, M. Trippler, J. Pietrek, J. Schlue, M. P. Manns, H. Wedemeyer, E. Jaeckel, and M. Hardtke-Wolenski
  
• The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatol Commun, 2021
  J. Dywicki, L. E. Buitrago-Molina, F. Noyan, A. C. Davalos-Misslitz, K. L. Hupa-Breier, M. Lieber, M. Hapke, J. Schlue, C. S. Falk, S. Raha, I. Prinz, C. Koenecke, M. P. Manns, H. Wedemeyer, M. Hardtke-Wolenski, and E. Jaeckel