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

Oct 16, 2012American journal of physiology. Gastrointestinal and liver physiology

Chronic alcohol use changes liver cell support structures, blocking movement of STAT3 and STAT5B into the nucleus but not Smad2/3

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Ethanol exposure impaired nuclear translocation of STAT5B but not Smad2/3, suggesting a specific effect on certain signaling pathways.

Alcohol exposure increased microtubule acetylation and stability in liver cells.
Impairment of STAT5B and STAT3 translocation was observed following ethanol treatment.
Smad2/3 translocation was unaffected by alcohol, indicating a selective impact on certain factors.
Microtubule stabilization via taxol or trichostatin A replicated the impairment of STAT5B translocation seen with ethanol.
Increased microtubule acetylation and stability explains the reduced nuclear translocation of STAT5B.
Nuclear exit of STAT5B was unaffected, showing independence from microtubule dynamics.

AI simplified

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.

Full Text

Full text is available at the source.

View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief