Alcohol-induced defects in hepatic transcytosis may be explained by impaired dynein function

Jennifer L. Groebner, David J. Fernandez, Dean J. Tuma, Pamela L. Tuma

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Alcoholic liver disease has been clinically well described, but the molecular mechanisms leading to hepatotoxicity have not been fully elucidated. Previously, we determined that microtubules are hyperacetylated and more stable in ethanol-treated WIF-B cells, VL-17A cells, liver slices, and in livers from ethanol-fed rats. From our recent studies, we believe that these modifications can explain alcohol-induced defects in microtubule motor-dependent protein trafficking including nuclear translocation of a subset of transcription factors. Since cytoplasmic dynein/dynactin is known to mediate both microtubule-dependent translocation and basolateral to apical/canalicular transcytosis, we predicted that transcytosis is impaired in ethanol-treated hepatic cells. We monitored transcytosis of three classes of newly synthesized canalicular proteins in polarized, hepatic WIF-B cells, an emerging model system for the study of liver disease. As predicted, canalicular delivery of all proteins tested was impaired in ethanol-treated cells. Unlike in control cells, transcytosing proteins were observed in discrete sub-canalicular puncta en route to the canalicular surface that aligned along acetylated microtubules. We further determined that the stalled transcytosing proteins colocalized with dynein/dynactin in treated cells. No changes in vesicle association were observed for either dynein or dynactin in ethanol-treated cells, but significantly enhanced dynein binding to microtubules was observed. From these results, we propose that enhanced dynein binding to microtubules in ethanol-treated cells leads to decreased motor processivity resulting in vesicle stalling and in impaired canalicular delivery. Our studies also importantly indicate that modulating cellular acetylation levels with clinically tolerated deacetylase agonists may be a novel therapeutic strategy for treating alcoholic liver disease.

Original languageEnglish (US)
Pages (from-to)223-233
Number of pages11
JournalMolecular and cellular biochemistry
Volume397
Issue number1-2
DOIs
StatePublished - Oct 29 2014

Fingerprint

Transcytosis
Dyneins
Microtubules
Ethanol
Liver
Cells
Alcohols
Defects
Alcoholic Liver Diseases
Proteins
B-Lymphocytes
Cytoplasmic Dyneins
Acetylation
Protein Transport
Rats
Liver Diseases
Hepatocytes
Transcription Factors
Association reactions
Dynactin Complex

Keywords

  • Dynactin
  • Dynein
  • Ethanol
  • Microtubules
  • Transcytosis
  • WIF-B cells

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Alcohol-induced defects in hepatic transcytosis may be explained by impaired dynein function. / Groebner, Jennifer L.; Fernandez, David J.; Tuma, Dean J.; Tuma, Pamela L.

In: Molecular and cellular biochemistry, Vol. 397, No. 1-2, 29.10.2014, p. 223-233.

Research output: Contribution to journalArticle

Groebner, Jennifer L. ; Fernandez, David J. ; Tuma, Dean J. ; Tuma, Pamela L. / Alcohol-induced defects in hepatic transcytosis may be explained by impaired dynein function. In: Molecular and cellular biochemistry. 2014 ; Vol. 397, No. 1-2. pp. 223-233.
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