Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells.
Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20;:
Authors: Rymut SM, Lu B, Perez A, Corey DA, Lamb K, Cotton CU, Kelley TJ
The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis has been shown to be an effective intervention though use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in cystic fibrosis (CF) epithelial cells through a 5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(Tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to WT rates. TOFA treatment also restores microtubule dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the pro-inflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.
PMID: 30892081 [PubMed – as supplied by publisher]