TGF-β interference with MEOS and ADH metabolising systems may promote alcohol dependent liver damage

Aims: Fibrogenesis involves cytokines, acetaldehyde, oxidative stress and complex interactions between liver cells. Hepatotoxic effects of chronic alcohol comsumption result from activating ADH and MEOS systems. TGF-β is induced in liver of patients with alcoholic liver disease, suggesting its involvement adverse effects of alcohol, however, a molecular connection was not yet identified.

Aim: To show a crosstalk between TGF-β signaling and alcohol dependent damage in hepatocytes. Methods: Using DNA microarrays, a TGF-β dependent expression profile was established for hepatocytes. Results were confirmed by RT-PCR and Western blot analysis.

Results: Microarray data implicate that TGF-β induces expression of Cyp21A1 in hepatocytes. This finding was confirmed by RT-PCR, showing that TGF-β and alcohol stimulate expression of Cyp2E1 and Cyp21A1 to a similar extent. During culture of mouse hepatocytes, Cyp2E1 expression is down-regulated. Co-stimulation with TGF-β and alcohol did not display enhanced Cyp2E1 expression, suggesting that TGF-β might be a downstream mediator of alcohol effects. Interestingly, while inducing MEOS activity, TGF-β downregulates alcohol dehydrogenase ADH1 expression, which represents the enzyme of the primarily used alcohol metabolising mechanism. Currently we delineate the TGF-β signalling pathway leading to regulation of Cyp2E1, Cyp21A1 and ADH1 using Smad7 overexpression an siRNA interference.

Conclusions: TGF-β regulates expression of enzymes involved in alcohol metabolism. Genes encoding enzymes of MEOS are upregulated, whereas ADH1 expression is decreased. These data suggest hat TGF-β contributes to alcohol induced liver damage by favouring an oxidative stress producing metabolic route.