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Cell Death Dis. 2018 Jan 19;9(2):51. doi: 10.1038/s41419-017-0071-y.

Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis.

Author information

1
Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
2
Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, 51429, Bergisch Gladbach, Germany.
3
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.
4
Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
5
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
6
Eberhard-Karls University Tübingen, BG Trauma Center, SWI, Schnarrenbergstraße 95, 72076, Tübingen, Germany.
7
University of Vienna, Department of Nutritional Sciences, Molecular Nutritional Science, Althanstr. 14, UZA II, A-1090, Wien, Austria.
8
Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, UK.
9
Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. steven.dooley@medma.uni-heidelberg.de.

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.

PMID:
29352207
PMCID:
PMC5833779
DOI:
10.1038/s41419-017-0071-y
[Indexed for MEDLINE]
Free PMC Article

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