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

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. FriedmanAli Canbay, Lars P. Bechmann

Research output: Contribution to journalArticle

5 Citations (Scopus)

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)- A nd 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.

Original languageEnglish (US)
Article number8119
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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Autophagy
Acute Liver Failure
Hepatocytes
Liver
Wounds and Injuries
Acetaminophen
Growth Inhibitors
Liver Regeneration
Carbon Tetrachloride
Hepatectomy
Luciferases
Hepatocellular Carcinoma
Homeostasis
Transcription Factors
Cell Proliferation
Lipids
Glucose
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Sydor, S., Manka, P., Best, J., Jafoui, S., Sowa, J. P., Zoubek, M. E., ... Bechmann, L. P. (2017). Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury. Scientific reports, 7(1), [8119]. https://doi.org/10.1038/s41598-017-08680-w

Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury. / Sydor, Svenja; Manka, Paul; Best, Jan; Jafoui, Sami; Sowa, Jan Peter; Zoubek, Miguel Eugenio; Hernandez-Gea, Virginia; Cubero, Francisco Javier; Kälsch, Julia; Vetter, DIana; Fiel, Maria Isabel; Hoshida, Yujin; Bian, C. Billie; Nelson, Leonard J.; Moshage, Han; Faber, Klaas Nico; Paul, Andreas; Baba, Hideo A.; Gerken, Guido; Friedman, Scott L.; Canbay, Ali; Bechmann, Lars P.

In: Scientific reports, Vol. 7, No. 1, 8119, 01.12.2017.

Research output: Contribution to journalArticle

Sydor, S, Manka, P, Best, J, Jafoui, S, Sowa, JP, Zoubek, ME, Hernandez-Gea, V, Cubero, FJ, Kälsch, J, Vetter, DI, Fiel, MI, Hoshida, Y, Bian, CB, Nelson, LJ, Moshage, H, Faber, KN, Paul, A, Baba, HA, Gerken, G, Friedman, SL, Canbay, A & Bechmann, LP 2017, 'Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury', Scientific reports, vol. 7, no. 1, 8119. https://doi.org/10.1038/s41598-017-08680-w
Sydor, Svenja ; Manka, Paul ; Best, Jan ; Jafoui, Sami ; Sowa, Jan Peter ; Zoubek, Miguel Eugenio ; Hernandez-Gea, Virginia ; Cubero, Francisco Javier ; Kälsch, Julia ; Vetter, DIana ; Fiel, Maria Isabel ; Hoshida, Yujin ; Bian, C. Billie ; Nelson, Leonard J. ; Moshage, Han ; Faber, Klaas Nico ; Paul, Andreas ; Baba, Hideo A. ; Gerken, Guido ; Friedman, Scott L. ; Canbay, Ali ; Bechmann, Lars P. / Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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AU - Sowa, Jan Peter

AU - Zoubek, Miguel Eugenio

AU - Hernandez-Gea, Virginia

AU - Cubero, Francisco Javier

AU - Kälsch, Julia

AU - Vetter, DIana

AU - Fiel, Maria Isabel

AU - Hoshida, Yujin

AU - Bian, C. Billie

AU - Nelson, Leonard J.

AU - Moshage, Han

AU - Faber, Klaas Nico

AU - Paul, Andreas

AU - Baba, Hideo A.

AU - Gerken, Guido

AU - Friedman, Scott L.

AU - Canbay, Ali

AU - Bechmann, Lars P.

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