Eylem Seç
Alcohol-Induced Tubulin Hyperacetylation Impairs Microtubule Dynamics and Motor Function: Contributions to Hepatic Injury
Başlık:
Alcohol-Induced Tubulin Hyperacetylation Impairs Microtubule Dynamics and Motor Function: Contributions to Hepatic Injury
Yazar:
Groebner, Jennifer L., author. (orcid)0000-0003-1503-5030
ISBN:
9780438007970
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (141 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Pamela L. Tuma Committee members: John Golin; Farzana A. McRae; J. Michael Mullins; Sen Nieh.
Özet:
Although the progression of alcoholic liver disease (ALD) is clinically well described, there are currently no treatments to relieve or reverse the disease state. Our previous work has shown that ethanol metabolism induces microtubule acetylation and stability, which strongly correlates with defects in microtubule motor-mediated protein trafficking including secretion and nuclear translocation. Because transcytosis is also microtubule motor-dependent, we examined this process and found that it was also significantly impaired by ethanol treatment. Not only did dynein/dynactin, the minus end-directed motor complex, colocalize with stalled transcytosing proteins on acetylated microtubules, dynein was also more strongly associated with microtubules, which we suggest leads to decreased motor processivity resulting in vesicle stalling and impaired delivery. Since microtubule acetylation has been shown to mediate lipid droplet biogenesis and because fatty liver is an early stage of ALD, we examined lipid droplet dynamics in ethanol-treated cells. Ethanol metabolism enhanced lipid droplet accumulation and enlargement with a reciprocal decrease in droplet degradation. Since droplet motility is also microtubule motor-dependent and implicated in droplet growth and degradation, we performed live cell imaging of fluorescently-labeled droplets. Lipid droplet motility was significantly impaired and large droplets were essentially stationary in ethanol-treated cells. In cells depleted of intact microtubules, lipid droplets were immobile and redistributed from the cell periphery to more apical regions, indicating that intact microtubules are required for droplet motility and distributions. To directly assess if microtubule acetylation can directly explain defects in motor-mediated motility, we overexpressed alpha-tubulin acetyltransferase (alphaTAT1) to induce acetylation levels (~3-fold) similar to those observed in ethanol-treated cells. Live cell imaging revealed that lipid droplet motility was decreased in cells overexpressing alphaTAT1, but to a lesser extent than in ethanol-treated cells. Dynein/dynactin colocalized with large, immotile droplets in both ethanol-treated cells and in cells overexpressing alphaTAT1, suggesting that enhanced droplet binding leads to stalled droplets. We further determined that ethanol-induced impairment of microtubule-dependent STAT5B nuclear translocation attenuated growth hormone-mediated hepatoprotective signaling, further suggesting that modulating tubulin acetylation levels is a novel therapeutic target for ALD.
Notlar:
School code: 0043
Tüzel Kişi Ek Girişi:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(679989.1) | 679989-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.