Hepatic microtubule acetylation and stability induced by chronic alcohol exposure impair nuclear translocation of STAT3 and STAT5B, but not Smad2/3.

Although alcoholic liver disease is clinically well described, the molecular basis for alcohol-induced hepatotoxicity is not well understood. Previously, we found that alcohol exposure led to increased microtubule acetylation and stability in polarized, hepatic WIF-B cells and in livers from ethanol-fed rats. Because microtubules are known to regulate transcription factor nuclear translocation and dynamic microtubules are required for translocation of at least a subset of these factors, we examined whether alcohol-induced microtubule acetylation and stability impair nuclear translocation. We examined nuclear delivery of factors representing the two mechanisms by which microtubules regulate translocation. To represent factors that undergo directed delivery, we examined growth hormone-induced STAT5B translocation and IL-6-induced STAT3 translocation. To represent factors that are sequestered in the cytoplasm by microtubule attachment until ligand activation, we examined transforming growth factor-β-induced Smad2/3 translocation. We found that ethanol exposure selectively impaired translocation of the STATs, but not Smad2/3. STAT5B delivery was decreased to a similar extent by addition of taxol (a microtubule-stabilizing drug) or trichostatin A (a deacetylase inhibitor), agents that promote microtubule acetylation in the absence of alcohol. Thus the alcohol-induced impairment of STAT nuclear translocation can be explained by increased microtubule acetylation and stability. Only ethanol treatment impaired STAT5B activation, indicating that microtubules are not important for its activation by Jak2. Furthermore, nuclear exit was not changed in treated cells, indicating that this process is also independent of microtubule acetylation and stability. Together, these results raise the exciting possibility that deacetylase agonists may be effective therapeutics for the treatment of alcoholic liver disease.