Ethanol sensitizes hepatocytes for TGF-?-triggered apoptosis.

ABSTRACT: Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-?-a potent pro-fibrogenic cytokine-leads to disease progression. Our aim was to elucidate the crosstalk of TGF-? and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-? 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-? 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-? 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-3? activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-?. This study provides novel information on the crosstalk between ethanol and TGF-?. We give evidence that ethanol directly leads to a boost of TGF-?'s pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.

SUBMITTER: Gaitantzi H 

PROVIDER: S-EPMC5833779 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature