Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis

Autor(en)

Haristi Gaitantzi, Christoph Meyer, Pia Rakoczy, Maria Thomas, Kristin Wahl, Franziska Wandrer, Heike Bantel, Hamed Alborzinia, Stefan Wölfl, Sabrina Ehnert, Andreas Nüssler, Ina Bergheim, Loredana Ciuclan, Matthias Ebert, Katja Breitkopf-Heinlein, Steven Dooley

Abstrakt

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-β - a potent pro-fibrogenic cytokine - leads to disease progression. Our aim was to elucidate the crosstalk of TGF-β and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-β and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated. Results: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-β increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-β pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3β activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-β. This study provides novel information on the crosstalk between ethanol and TGF-β. We give evidence that ethanol directly leads to a boost of TGF-β's pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.

Organisation(en)

Department für Ernährungswissenschaften

Externe Organisation(en)

Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Medizinische Hochschule Hannover (MHH), Universität Heidelberg, Eberhard Karls Universität Tübingen, Roche Products Ltd.

Journal

Cell Death & Disease

Band

9

Anzahl der Seiten

15

ISSN

2041-4889

DOI

https://doi.org/10.1038/s41419-017-0071-y

Publikationsdatum

01-2018

Peer-reviewed

Ja

ÖFOS 2012

303009 Ernährungswissenschaften

Schlagwörter

ASJC Scopus Sachgebiete

Cellular and Molecular Neuroscience, Cancer Research, Cell Biology, Immunology

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/ethanol-sensitizes-hepatocytes-for-tgftriggered-apoptosis(3a3659ee-9e30-4a7c-92d7-a1b9d7ceaeb3).html