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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

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Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis.

Gaitantzi Haristi H Meyer Christoph C Rakoczy Pia P Thomas Maria M Wahl Kristin K Wandrer Franziska F Bantel Heike H Alborzinia Hamed H Wölfl Stefan S Ehnert Sabrina S Nüssler Andreas A Bergheim Ina I Ciuclan Loredana L Ebert Matthias M Breitkopf-Heinlein Katja K Dooley Steven S

Cell death & disease 20180119 2

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 inhi ...[more]

PMID: 29352207

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Project description:Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Dataset Information

Ethanol sensitizes hepatocytes for TGF-?-triggered apoptosis.

Publications

Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis.

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