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• W2792078180 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.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." @default.
• W2792078180 created "2018-03-29" @default.
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• W2792078180 date "2018-01-19" @default.
• W2792078180 modified "2023-10-14" @default.
• W2792078180 title "Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis" @default.
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• W2792078180 doi "https://doi.org/10.1038/s41419-017-0071-y" @default.
• W2792078180 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5833779" @default.
• W2792078180 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29352207" @default.
• W2792078180 hasPublicationYear "2018" @default.
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