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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2286249dec7344db8e423965de3b8b26
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spelling	oai:doaj.org-article:2286249dec7344db8e423965de3b8b262021-12-02T15:05:55ZKrüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury10.1038/s41598-017-08680-w2045-2322https://doaj.org/article/2286249dec7344db8e423965de3b8b262017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08680-whttps://doaj.org/toc/2045-2322Abstract 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.Svenja SydorPaul MankaJan BestSami JafouiJan-Peter SowaMiguel Eugenio ZoubekVirginia Hernandez-GeaFrancisco Javier CuberoJulia KälschDiana VetterMaria Isabel FielYujin HoshidaC. Billie BianLeonard J. NelsonHan MoshageKlaas Nico FaberAndreas PaulHideo A. BabaGuido GerkenScott L. FriedmanAli CanbayLars P. BechmannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2017
url	https://doaj.org/article/2286249dec7344db8e423965de3b8b26
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Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury

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