Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis
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...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
19 January 2018
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| In: |
Cell death & disease
Year: 2018, Jahrgang: 9, Heft: 2 |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-017-0071-y |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1038/s41419-017-0071-y Verlag, Volltext: https://www.nature.com/articles/s41419-017-0071-y 
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| Verfasserangaben: | 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 |
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| 245 | 1 | 0 | |a Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis |c 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 |
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| 520 | |a 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. | ||
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