EFFECTS OF ALCOHOL ON TGF-β MEDIATED HEPATOCYTE APOPTOSIS

Sandra HelinskiLeave a Comment

Breitkopf-Heinlein K1, Meyer C1, Thomas M2, Wahl K3, Bantel H3, Bergheim I4, and Dooley S1.

1 Universitätsmedizin Mannheim,II. Medical Clinic,Medical Faculty Mannheim at Heidelberg University, Molecular Hepatology – Alcohol Associated Diseases, Mannheim,Germany

2 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology,Stuttgart, Germany

3 Medizinische Hochschule Hannover OE 6810,Hannover, Germany

4 Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany

 

Background and aims

Alcohol abuse is a major health concern worldwide and accompanied with elevated levels of the pro-fibrogenic cytokine TGF-β. Aim of this study was to characterize crosstalk of TGF-β and alcohol on hepatocytes.

 

Methods

Primary isolated mouse hepatocytes were treated with ethanol and TGF-β and cellular fate was determined. Expression patterns of apoptosis-related genes were analyzed on RNA level using Fluidigm technology. To gain mechanistic insight into the crosstalk, we interfered with prominent pathways in vitro. To substantiate in vitro findings, human liver slice cultures and an acute alcohol intoxication animal model were investigated.

 

Results

TGF-β and ethanol each had a moderate effect on hepatocyte survival. Combined treatment culminated in a massive apoptotic response in primary hepatocytes which was confirmed in human liver tissue treated ex vivo. Alcohol increased the TGF-β pro-apoptotic gene expression signature. The underlying mechanism involves canonical Smad and non-Smad signaling. We define the AKT/GSK3β as a relevant target of ethanol/TGF-β treatment. Noteworthy, alcohol itself – but not its metabolism – mediated these effects as blocking of Cyp2e1 and ADH did not prevent super-induction of apoptosis. In addition, direct application of acetaldehyde could also not mimic the effect of ethanol.

 

Conclusion

Our study provides molecular data on how ethanol amplifies TGF-β dependent hepatocyte apoptosis. These data indicate that continued alcohol consumption in a pre-damaged liver with TGF-β abundance will likely accelerate and worsen disease development.

 

 

 

 

 

 

 

 

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