Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury
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 regenerat...
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2017-08-01
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doaj-2286249dec7344db8e423965de3b8b262020-12-08T00:44:29ZengNature Publishing GroupScientific Reports2045-23222017-08-017111210.1038/s41598-017-08680-wKrüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injurySvenja Sydor0Paul Manka1Jan Best2Sami Jafoui3Jan-Peter Sowa4Miguel Eugenio Zoubek5Virginia Hernandez-Gea6Francisco Javier Cubero7Julia Kälsch8Diana Vetter9Maria Isabel Fiel10Yujin Hoshida11C. Billie Bian12Leonard J. Nelson13Han Moshage14Klaas Nico Faber15Andreas Paul16Hideo A. Baba17Guido Gerken18Scott L. Friedman19Ali Canbay20Lars P. Bechmann21Department of Gastroenterology and Hepatology, University Hospital EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Medicine III, University Hospital RWTH AachenBarcelona 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)Department of Medicine III, University Hospital RWTH AachenDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Surgery, University Hospital ZurichDivision of Liver Diseases, Department of Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiDivision of Liver Diseases, Department of Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiDivision of Liver Diseases, Department of Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiInstitute for Bio Engineering (IBioE), Human Tissue Engineering, Faraday Building, The University of EdinburghDepartment of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of GroningenDepartment of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of GroningenDepartment of General- and Transplant-Surgery, University Hospital EssenDepartment of Pathology, University Hospital of EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenDivision of Liver Diseases, Department of Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiDepartment of Gastroenterology and Hepatology, University Hospital EssenDepartment of Gastroenterology and Hepatology, University Hospital EssenAbstract 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.https://doi.org/10.1038/s41598-017-08680-w |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Svenja Sydor Paul Manka Jan Best Sami Jafoui Jan-Peter Sowa Miguel Eugenio Zoubek Virginia Hernandez-Gea Francisco Javier Cubero Julia Kälsch Diana Vetter Maria Isabel Fiel Yujin Hoshida C. Billie Bian Leonard J. Nelson Han Moshage Klaas Nico Faber Andreas Paul Hideo A. Baba Guido Gerken Scott L. Friedman Ali Canbay Lars P. Bechmann |
spellingShingle |
Svenja Sydor Paul Manka Jan Best Sami Jafoui Jan-Peter Sowa Miguel Eugenio Zoubek Virginia Hernandez-Gea Francisco Javier Cubero Julia Kälsch Diana Vetter Maria Isabel Fiel Yujin Hoshida C. Billie Bian Leonard J. Nelson Han Moshage Klaas Nico Faber Andreas Paul Hideo A. Baba Guido Gerken Scott L. Friedman Ali Canbay Lars P. Bechmann Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury Scientific Reports |
author_facet |
Svenja Sydor Paul Manka Jan Best Sami Jafoui Jan-Peter Sowa Miguel Eugenio Zoubek Virginia Hernandez-Gea Francisco Javier Cubero Julia Kälsch Diana Vetter Maria Isabel Fiel Yujin Hoshida C. Billie Bian Leonard J. Nelson Han Moshage Klaas Nico Faber Andreas Paul Hideo A. Baba Guido Gerken Scott L. Friedman Ali Canbay Lars P. Bechmann |
author_sort |
Svenja Sydor |
title |
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
title_short |
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
title_full |
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
title_fullStr |
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
title_full_unstemmed |
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
title_sort |
krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-017-08680-w |
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