Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis

• Verfasst von: Gaitantzi, Haristi [VerfasserIn]
• Verfasst von: Meyer, Christoph [VerfasserIn]
• Verfasst von: Alborzinia, Hamed [VerfasserIn]
• Verfasst von: Wölfl, Stefan [VerfasserIn]
• Verfasst von: Ebert, Matthias [VerfasserIn]
• Verfasst von: Breitkopf-Heinlein, Katja [VerfasserIn]
• Verfasst von: Dooley, Steven [VerfasserIn]
• Titel: Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis
• Verf.angabe: 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 and Steven Dooley
• E-Jahr: 2018
• Jahr: 19 January 2018
• Umfang: 15 S.
• Fussnoten: Gesehen am 03.09.2019
• Titel Quelle: Enthalten in: Cell death & disease
• Ort Quelle: London [u.a.] : Nature Publishing Group, 2010
• Jahr Quelle: 2018
• Band/Heft Quelle: 9(2018,2) Artikel-Nummer 51, 15 Seiten
• ISSN Quelle: 2041-4889
• DOI: doi:10.1038/s41419-017-0071-y
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 167578180X

Abstract

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.