2. Academic Validation
  3. Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury

Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury

  • Sci Rep. 2017 Aug 14;7(1):8119. doi: 10.1038/s41598-017-08680-w.
Svenja Sydor 1 2,  Paul Manka 1 3,  Jan Best 1,  Sami Jafoui 1,  Jan-Peter Sowa 1,  Miguel Eugenio Zoubek 4,  Virginia Hernandez-Gea 5,  Francisco Javier Cubero 4 6,  Julia Kälsch 1 7,  Diana Vetter 8,  Maria Isabel Fiel 9,  Yujin Hoshida 9,  C Billie Bian 9,  Leonard J Nelson 10,  Han Moshage 11 12,  Klaas Nico Faber 11 12,  Andreas Paul 13,  Hideo A Baba 7,  Guido Gerken 1,  Scott L Friedman 9,  Ali Canbay 1 2,  Lars P Bechmann 14 15
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
  • 2 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, Germany.
  • 3 Regeneration and Repair, Institute of Hepatology, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, Tower Wing Guy's Hospital London, London, SE1 9RT, United Kingdom.
  • 4 Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
  • 5 Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Villarroel 170, 08036, Barcelona, Spain.
  • 6 Department of Immunology, Complutense University School of Medicine, Avenida de Séneca 2, 28040, Madrid, Spain.
  • 7 Department of Pathology, University Hospital of Essen, Hufelandstrasse 55, 45147, Essen, Germany.
  • 8 Department of Surgery, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
  • 9 Division of Liver Diseases, Department of Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY, 10029, USA.
  • 10 Institute for Bio Engineering (IBioE), Human Tissue Engineering, Faraday Building, The University of Edinburgh, The King's Buildings, Mayfield Road, Edinburgh, EH9 3JL, Scotland, United Kingdom.
  • 11 Department of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
  • 12 Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
  • 13 Department of General- and Transplant-Surgery, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
  • 14 Department of Gastroenterology and Hepatology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany. [email protected].
  • 15 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, Germany. [email protected].
PMID: 28808340 DOI: 10.1038/s41598-017-08680-w
Abstract

Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and Beclin1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates Autophagy by transcriptional induction of ATG7 and Beclin1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of Autophagy in hepatocytes.

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